WO2024099241A1 - Dérivé de pyrimidine deutéré et composition pharmaceutique le comprenant - Google Patents

Dérivé de pyrimidine deutéré et composition pharmaceutique le comprenant Download PDF

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WO2024099241A1
WO2024099241A1 PCT/CN2023/129825 CN2023129825W WO2024099241A1 WO 2024099241 A1 WO2024099241 A1 WO 2024099241A1 CN 2023129825 W CN2023129825 W CN 2023129825W WO 2024099241 A1 WO2024099241 A1 WO 2024099241A1
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compound
cancer
synthesis
pharmaceutically acceptable
btk
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鲍荣肖
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天津征程医药科技有限公司
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  • the present invention belongs to the field of biomedicine, and specifically relates to a deuterated pyrimidine derivative, a pharmaceutical composition containing the compound and application thereof.
  • B cell signal transduction via the B cell receptor (BCR) can produce a wide range of biological output signals, and abnormal BCR-mediated signal transduction can cause dysregulated B cell activation and/or the formation of pathogenic autoantibodies that lead to a variety of autoimmune diseases and/or inflammatory diseases.
  • Mutations in BTK in humans lead to X-linked agammaglobulinemia (XLA) (Conley et al., Annu. Rev. Immunol. 27: 199-227, 2009). This disease is associated with impaired B cell maturation, reduced immunoglobulin production, impaired immune responses that are independent of T cells, and significant reductions in sustained calcium signals during BCR stimulation.
  • XLA X-linked agammaglobulinemia
  • BTK inhibitors can be used as inhibitors of B cell-mediated pathogenic activities (such as the production of autoantibodies). BTK is also expressed in osteoclasts, mast cells and monocytes and has been shown to be important for the function of these cells.
  • inhibition of BTK activity can be used to treat allergic diseases and/or autoimmune diseases and/or inflammatory diseases, such as rheumatoid arthritis, polyangiitis, idiopathic thrombocytopenic purpura (ITP), myasthenia gravis, allergic rhinitis and asthma (Di Paolo et al. (2011) Nature Chem. Biol. 7(1):41-50; Liu et al. (2011) Jour. of Pharm. and Exper. Ther. 338(1):154-163).
  • allergic diseases and/or autoimmune diseases and/or inflammatory diseases such as rheumatoid arthritis, polyangiitis, idiopathic thrombocytopenic purpura (ITP), myasthenia gravis, allergic rhinitis and asthma (Di Paolo et al. (2011) Nature Chem. Biol. 7(1):41-50; Liu et al. (2011) Jour. of Pharm. and Exper. Ther. 338(1):154-163).
  • BTK hematological malignancies
  • BTK plays a central role as a mediator in multiple signal transduction pathways
  • inhibiting BTK activity can be anti-inflammatory and/or anti-cancer, and can be used for cancer and the treatment of B-cell lymphoma, leukemia and other hematological malignancies (Mohamed et al., Immunol. Rev. 228:58-73, 2009; Pan, Drug News perspective 21:357-362, 2008; Rokosz et al., Expert Opin. Ther.
  • BTK inhibition of BTK activity may be useful in treating bone diseases, such as osteoporosis. Therefore, compounds having BTK inhibitory activity may be useful in treating diseases associated with B cells and/or mast cells, such as allergies. It is useful for the treatment of reactive diseases, autoimmune diseases, inflammatory diseases, thromboembolic diseases, cancer, etc. (Uckun et al. (2007) Anticancer Agents in Medicinal Chemistry. 7(6):624-632).
  • Evobrutinib is a BTK inhibitor developed by Merck KGaA in Germany. Data from a Phase II trial published at the 73rd Annual Meeting of the American Academy of Neurology (AAN) in 2021 showed that in patients with multiple sclerosis (MS), treatment with the highly selective oral BTK inhibitor evobrutinib significantly reduced blood neurofilament light chain (NfL) levels, a key biomarker of neural damage and inflammation that can monitor disease activity and treatment response.
  • MS multiple sclerosis
  • NfL blood neurofilament light chain
  • Evobutinib The specific metabolic pathway of Evobutinib is not very clear, and the elimination half-life of Evobutinib in humans is short, at 1.33 hours (Scheible H, et al. Clin Transl Sci. 2021; 14: 2420–2430). Furthermore, the effects of the absorption, distribution, metabolism and/or excretion of Evobutinib on its efficacy and/or toxicity are still not fully understood, and there is the possibility of improvement.
  • ADME absorption, distribution, metabolism and/or excretion
  • ADME limitation affecting drugs is the formation of toxic or biologically reactive metabolites. Therefore, some patients receiving drugs may experience toxicity, or the safe dose of such drugs may be limited so that patients receive treatment that is not the best amount (suboptimal). In some cases, changing the dosing interval or formulation method can help reduce clinical adverse reactions, but the frequent formation of such undesirable metabolites is inherent in the metabolism of the compound.
  • a potentially attractive strategy for improving drug metabolism is deuterium modification.
  • Deuterium is a safe, stable, non-radioactive isotope of hydrogen.
  • Deuterium forms stronger chemical bonds with carbon than hydrogen.
  • the increased bond strength imparted by deuterium can positively affect the ADME properties of a drug, with the potential to improve efficacy,
  • the size and shape of deuterium are substantially equivalent to hydrogen, it is expected that replacing hydrogen with deuterium will not affect the biochemical potency and selectivity of the drug compared to the original chemical entity containing only hydrogen.
  • deuteration slows their metabolic clearance in the body and increases their half-life; for other compounds, deuteration does not cause metabolic changes; for still other compounds, deuteration speeds up their metabolic clearance and shortens their half-life (Blake, MI et al, J Pharm Sci, 1975, 64:367-91; Foster, AB, Adv Drug Res 1985, 14:1-40 ("Foster”); Kushner, DJ et al, Can J Physiol Pharmacol 1999, 79-88; Fisher, MB et al, Curr Opin Drug Discov Dev 2006, 9:101-09 (“Fisher”)).
  • deuterium substitution at certain sites of a compound not only fails to increase the half-life, but may shorten it (Scott L. Harbeson, Roger D. Tung. Deuterium in Drug Discovery and Development, P405-406), deteriorating its pharmacokinetic properties; on the other hand, hydrogen at certain positions on drug molecules is not easily substituted by deuterium due to steric hindrance and other reasons. Even when deuterium atoms are incorporated into known metabolic sites, the effect of deuterium modification on drug metabolism is not predictable. Only by actually preparing and testing deuterated drugs can we determine whether and how the rate of metabolism will differ from the corresponding chemical entity without deuteration. Many drugs have multiple sites that may be metabolized. The position (site) that needs deuterium substitution and the degree of deuteration required to find an effect on metabolism, if any, will be different for each drug (Fukuto et al. J. Med. Chem. 1991, 34, 2871-76).
  • metabolic switching indicates that when a drug is encapsulated by a phase I metabolizing enzyme, it can briefly bind and rebind with the phase I metabolizing enzyme in various conformations before a chemical reaction (such as an oxidation reaction). Therefore, metabolic switching can potentially lead to different proportions of known metabolites and new metabolites. This new metabolic property can cause more or less toxicity. And lead to faster or slower drug clearance, thereby reducing or increasing the drug's in vivo exposure. Such changes caused by metabolic switching are unpredictable, and so far no adequate a priori prediction has been made for any drug.
  • Evobutinib and its metabolites in vivo have the defect of hepatotoxicity risk, and clinical trials of Evobutinib have also shown hepatotoxicity, causing great clinical concerns. Hepatotoxicity is not only related to the chemical structure, but also closely related to the clinical dosage.
  • the purpose of the present invention is to provide a new type of compound having BTK inhibitory activity and better pharmacodynamic properties and its use.
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 or R 20 are each independently selected from hydrogen (H) or deuterium (D), provided that at least one of R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 or R 20 is deuterium .
  • the compound is a preferred compound selected from the following group or a pharmaceutically acceptable salt, isomer, metabolite, prodrug, solvate or hydrate thereof:
  • the compound is a preferred compound selected from the following group or a pharmaceutically acceptable salt, isomer, metabolite, prodrug, solvate or hydrate thereof:
  • a method for preparing a pharmaceutical composition comprising the steps of: mixing a pharmaceutically acceptable carrier with the compound described in the first aspect of the present invention or a pharmaceutically acceptable salt, isomer, metabolite, prodrug, solvate or hydrate thereof to form a pharmaceutical composition.
  • a pharmaceutical composition which contains a pharmaceutically acceptable carrier or excipient and the compound described in the first aspect of the present invention or its pharmaceutically acceptable salt, isomer, metabolite, prodrug, solvate or hydrate.
  • the pharmaceutical composition is a capsule, tablet, injection, pill, powder or granule.
  • the compound described in the first aspect of the present invention or its pharmaceutically acceptable salt, isomer, metabolite, prodrug, solvate or hydrate, which is used to prepare a pharmaceutical composition for inhibiting BTK.
  • the pharmaceutical composition is used to prevent and/or treat diseases related to BTK.
  • the pharmaceutical composition is used to prevent and/or treat allergic diseases, autoimmune diseases, inflammatory diseases, thromboembolic diseases or cancer.
  • the pharmaceutical composition is used to treat autoimmune diseases, including multiple sclerosis (MS), systemic lupus erythematosus (SLE), chronic spontaneous urticaria, neuromyelitis optica or rheumatoid arthritis (RA).
  • MS multiple sclerosis
  • SLE systemic lupus erythematosus
  • RA rheumatoid arthritis
  • the pharmaceutical composition is used to treat cancers including (but not limited to): lymphoma, leukemia, non-small cell lung cancer, uterine cancer, colorectal cancer, brain cancer, head cancer, neck cancer, bladder cancer, prostate cancer, breast cancer, kidney cancer, liver cancer, gastric cancer, or pancreatic cancer.
  • cancers including (but not limited to): lymphoma, leukemia, non-small cell lung cancer, uterine cancer, colorectal cancer, brain cancer, head cancer, neck cancer, bladder cancer, prostate cancer, breast cancer, kidney cancer, liver cancer, gastric cancer, or pancreatic cancer.
  • a treatment method which comprises the steps of administering the compound described in the first aspect of the present invention or a pharmaceutically acceptable salt, isomer, metabolite, prodrug, solvate or hydrate thereof, or administering the pharmaceutical composition described in the third aspect of the present invention to a subject in need of treatment, thereby inhibiting BTK.
  • deuterated refers to a compound or group in which one or more hydrogen atoms are replaced by deuterium. Deuterated can be monosubstituted, disubstituted, polysubstituted or fully substituted.
  • the deuterium isotope content of deuterium at the deuterium substitution position is greater than the natural deuterium isotope content (0.015%), more preferably greater than 50%, more preferably greater than 85%, more preferably greater than 95%, more preferably greater than 99%, more preferably greater than 99.5%.
  • the compound of formula I contains at least 1 or 3 deuterium atoms, more preferably 5 or 8 deuterium atoms.
  • the term "compound of the present invention” refers to a compound represented by Formula I.
  • the term also includes a crystalline form of the compound of Formula I, a salt thereof, a hydrate thereof, or a solvate thereof.
  • pharmaceutically acceptable salt refers to a salt formed by a compound of the present invention and an acid or base that is suitable for use as a drug
  • pharmaceutically acceptable salts include inorganic salts and organic salts.
  • a preferred class of salts is a salt formed by a compound of the present invention and an acid.
  • Acids suitable for forming salts include, but are not limited to, inorganic acids such as hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, nitric acid, phosphoric acid, formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, picric acid, methanesulfonic acid, benzenesulfonic acid, benzenesulfonic acid, and acidic amino acids such as aspartic acid and glutamic acid.
  • inorganic acids such as hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, nitric acid, phosphoric acid, formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric
  • the compounds of the present invention have good selective BTK inhibitory effects and can be effectively used for treating diseases associated with BTK.
  • the compound of the present invention has good selectivity in inhibiting B cell activation and is effectively used as a B cell activation inhibitor.
  • the deuterated pyrimidine derivatives of the present invention have low hepatotoxicity, good pharmacokinetic properties, reduced dosage and/or reduced toxic and side effects, and better drugability.
  • the preparation method of the compound of formula I of the present invention is described in more detail below, but these specific methods do not constitute any limitation to the present invention.
  • the compounds of the present invention can also be conveniently prepared by optionally combining various synthetic methods described in this specification or known in the art, and such a combination can be easily carried out by a technician in the field to which the present invention belongs.
  • the preparation methods of the non-deuterated pyrimidine derivatives and their physiologically compatible salts used in the present invention are known.
  • the corresponding deuterated pyrimidine derivatives can be synthesized using the corresponding deuterated starting compounds as raw materials and in the same way.
  • the hydrogen nuclear magnetic resonance spectrum of compound H106 is: 1 H-NMR (DMSO-d 6 ) ⁇ 8.3(1H),7.4(2H),7.3-7.0(3H),6.8(2H),4.3(1H),4.0(1H),3.1(2H),3.0(1H),2.6(1H),1.8(1H),1.6(2H),0.9(2H).
  • step 4 in “Example 1: Synthesis of compound H106” was replaced with the following step 5.
  • the remaining steps were carried out in the same manner as in “Example 1: Synthesis of compound H106” to obtain compound H106 as a white solid.
  • the hydrogen nuclear magnetic resonance spectrum of compound H106 is: 1 H-NMR (DMSO-d 6 ) ⁇ 8.3(1H),7.4(2H),7.3-7.0(3H),6.8(2H),4.3(1H),4.0(1H),3.1(2H),3.0(1H),2.6(1H),1.8(1H),1.6(2H),0.9(2H).
  • step 4 in “Example 1: Synthesis of compound H106” was replaced with the following step 6.
  • the remaining steps were carried out in the same manner as in “Example 1: Synthesis of compound H106” to obtain compound H106 as a white solid.
  • step 1 in “Example 1: Synthesis of compound H106” was replaced with the following step 7. The remaining steps were carried out in the same manner as in “Example 1: Synthesis of compound H106” to obtain compound H106 as a white solid.
  • Step 7 Dissolve compound H001 (100 mg, 0.61 mmol), compound H002 (117.24 mg, 0.91 mmol) and DBU (0.18 mL 1.22 mmol) in DMF (2 ml), stir the reaction mixture overnight at 90 ° C, and cool to room temperature.
  • the crude mixture is purified by column chromatography, eluting with 0-100% MeOH/EtOAc. The product fractions are combined and concentrated under reduced pressure. The residue is lyophilized to obtain compound H003 as a white solid.
  • Rats were fed with standard feed and fasted 12 hours before administration.
  • the administration solution was prepared with 0.5% sodium carboxymethylcellulose (CMC-Na).
  • Blood was collected from the orbital venous plexus at 0.25 hours, 0.5 hours, 1 hour, 2 hours, 4 hours, 6 hours, 8 hours, 10 hours and 24 hours after administration.
  • the blood sample After the blood sample is collected, place it in a centrifuge tube coated with sodium heparin solution and gently invert the tube at least 5 times to ensure that Mix thoroughly and place on ice. Centrifuge the blood sample at 5000 rpm for 5 minutes at 4°C to separate the plasma from the red blood cells. Use a pipette to aspirate 100 ⁇ L of plasma into a clean plastic centrifuge tube and mark the sample number and blood collection time point. The plasma is stored in a -80°C refrigerator before LC-MS/MS analysis.
  • test results show that compared with evobactinib, the elimination half-life T 1/2 and/or the area under the curve AUC and/or the maximum blood drug concentration C max of compound H101 increased by more than 40%; compared with evobactinib, the elimination half-life T 1/2 and/or the area under the curve AUC and/or the maximum blood drug concentration C max of compound H104 increased by more than 50%; compared with evobactinib, the elimination half-life T 1/2 and/or the area under the curve AUC and/or the maximum blood drug concentration C max of compound H106 increased by more than 50%; compared with evobactinib, the elimination half-life T 1/2 and/or the area under the curve AUC and/or the maximum blood drug concentration C max of compound H108 increased by more than 50%; compared with evobactinib, the elimination half-life T 1/2 and/or the area under the curve AUC and/or the maximum blood drug concentration C max of compound H109 increased by more than 50%; Compared with Evo
  • compound H101, compound H104, compound H106, compound H108, compound H109 and compound H114 of the present invention have better pharmacokinetic properties in animals, indicating better pharmacodynamics and therapeutic effects.
  • the ADP-Glo TM kit is used to measure the effect of the compound of the present invention on the activity of BTK.
  • the experimental method is as follows: ADP is the product of the kinase reaction, and the kinase activity can usually be detected by detecting the amount of ADP generated.
  • the ADP-Glo TM kit developed by Promega is to measure the in vitro activity of BTK by detecting the ADP level generated in the kinase reaction. In the kinase detection experiment, the kinase consumes ATP to phosphorylate the substrate and produces ADP. Then the ADP-Glo reagent is added to terminate the kinase reaction and the remaining ATP is completely consumed.
  • the kinase detection reagent is added to convert the generated ADP into new ATP.
  • the luciferase in the detection reagent can catalyze luciferin with the participation of ATP and O2 to generate a light signal, thereby converting the chemical signal into a light signal, and the intensity of the light signal is positively correlated with the amount of ADP generated in the kinase reaction, so that the activity of the kinase BTK can be quantitatively detected.
  • the detection buffer included 40mM Tris-HCl (pH 7.5), 10mM MgCl 2 (Sigma), 2mM MnCl 2 (Sigma), 0.05mM DTT (Sigma) and 0.01% BSA (Sigma); the kinase BTK was prepared into a kinase reaction solution with a concentration of 1.3ng/ ⁇ L using the detection buffer; the substrate reaction solution included 0.25mg/mL peptide substrate and 60 ⁇ M ATP.
  • the compound of the present invention was diluted with DMSO to a 0.5 mM solution, and then three-fold gradient dilution was performed with DMSO to a minimum concentration of 0.025 ⁇ M.
  • 50 nL of compound solutions of serial concentrations and 2.5 ⁇ L of kinase reaction solution were first added to a 384-well plate using Echo555, mixed evenly, and incubated at room temperature in the dark for 30 minutes; then 2.5 ⁇ L of substrate reaction solution was added, and the total reaction volume was 5.05 ⁇ L, and the reaction mixture was reacted at room temperature in the dark for 60 minutes; then 5 ⁇ L of ADP-Glo TM reagent was added to terminate the reaction, mixed evenly, and left at room temperature for 40 minutes; finally, 10 ⁇ L of kinase detection reagent was added, left at room temperature in the dark for 30 minutes, and then the value was read on Envision.
  • the inhibition percentage was calculated according to the following formula:
  • Inhibition % [1-(RLU compound-RLUmin)/(RLUmax-RLUmin)] ⁇ 100
  • RLU compound is the reading at a given concentration of the compound of the present invention
  • RLUmin is the reading without the addition of kinase BTK
  • RLUmax is the reading without the addition of the compound of the present invention.
  • the IC 50 value of the compound was calculated by using the XLfit program in Excel.
  • the compounds of the present invention have a good inhibitory effect on BTK, especially compounds H101, H104, H106, H109 and H111 are significantly higher than evobrutinib.
  • Example 28 Comparative study of liver toxicity in mice
  • mice Thirty-two adult male ICR mice with a body weight of (25 ⁇ 2 g) were selected, and all mice were allowed to freely access water and feed, and maintained under a day-night cycle at a temperature of 25 ⁇ 2° C. and a relative humidity of 50 ⁇ 10%.
  • mice Thirty-two male ICR mice were divided into four groups, 8 mice in each group, namely normal control group, model group, model + example compound group and model + evobactinib group.
  • the model + example compound group was intragastrically administered once a day at a dose of 50 mg/kg.
  • Example compound; the model + Evobutinib group was gavaged once a day at a dose (50 mg/kg) of Evobutinib for 8-16 weeks, respectively, and the normal control group and the model group were gavaged with an equal volume of purified water. Food was cut off after the last administration.
  • mice in the model group, the model + example compound group and the model + Evobutinib group were intraperitoneally injected with 250 mg/kg of APAP saline solution.
  • blood was collected from the eyeballs of mice in each group in turn, and the serum was separated by centrifugation at 3000r/min for 10 minutes, and stored at 4°C for standby use; the liver and spleen were quickly dissected. Rinse with 4°C saline, dry with filter paper, weigh, and fix part of the liver in 10% formaldehyde solution for slicing, and the remaining liver was stored in a -80°C low-temperature refrigerator.
  • the experimental data were expressed as mean ⁇ standard deviation ( ⁇ s) and analyzed using SPSS 22.0 statistical software. One-way analysis of variance was used to compare the differences between the groups. P ⁇ 0.05 was considered a significant difference.
  • the MDA content in the liver tissue homogenate of the mice in the model group increased significantly, and the GSH level decreased significantly (P ⁇ 0.05), resulting in the accumulation of lipid peroxidation products in the mice and the decrease of the antioxidant metabolism level; compared with the model group, there was no significant change in the MDA content and GSH level of the model + example compound group (P>0.05); compared with the model group, the MDA content of the model + evobactinib group increased significantly (P ⁇ 0.05), and the GSH level decreased significantly (P ⁇ 0.05), indicating that the example compound of the present application (50 mg/kg) had no significant effect on the lipid peroxidation caused by APAP, while evobactinib (50 mg/kg) had an effect on the lipid peroxidation caused by APAP, suggesting that the liver toxicity of the example compound of the present application to mice was significantly lower than that of evobactinib.
  • A+ is 2.5-3.5; A- is 1-2.3; A++ is 3.8-5; B+ is 29-40; B- is 42-60; B++ is 3.8-5; Is 15-26.
  • the compound of the present invention (50 mg/kg) has no significant effect on lipid peroxidation induced by APAP, while Evobutinib (50 mg/kg) has an effect on lipid peroxidation induced by APAP, indicating that the liver toxicity of the compound of the present invention to mice is significantly lower than that of Evobutinib.

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Abstract

La présente invention concerne un dérivé de pyrimidine deutéré représenté par la formule I ou un sel pharmaceutiquement acceptable, un isomère, un métabolite, un promédicament, un solvate ou un hydrate de celui-ci. La présente invention concerne en outre des compositions pharmaceutiques comprenant un support pharmaceutiquement acceptable et le dérivé de pyrimidine deutéré ou un sel, isomère, métabolite, promédicament, solvate ou hydrate pharmaceutiquement acceptable de celui-ci. Le composé représenté par la formule générale I selon la présente invention sert d'inhibiteur de BTK, est un agent prophylactique et/ou thérapeutique pour des maladies associées à BTK, et a un bon effet thérapeutique sur des maladies allergiques, des maladies auto-immunes, des maladies inflammatoires, des maladies thromboemboliques ou des cancers.
PCT/CN2023/129825 2022-11-07 2023-11-04 Dérivé de pyrimidine deutéré et composition pharmaceutique le comprenant WO2024099241A1 (fr)

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CN202211366534 2022-11-07
CN202211366534.7 2022-11-07
CN202311446421 2023-11-02
CN202311446421.2 2023-11-02

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