WO2022268148A1 - Composé pour dégrader la protéine btk, son procédé de préparation et son utilisation - Google Patents

Composé pour dégrader la protéine btk, son procédé de préparation et son utilisation Download PDF

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Publication number
WO2022268148A1
WO2022268148A1 PCT/CN2022/100642 CN2022100642W WO2022268148A1 WO 2022268148 A1 WO2022268148 A1 WO 2022268148A1 CN 2022100642 W CN2022100642 W CN 2022100642W WO 2022268148 A1 WO2022268148 A1 WO 2022268148A1
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WO
WIPO (PCT)
Prior art keywords
phenoxyphenyl
pyrazolo
pyrimidin
amino
dioxoisoindol
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PCT/CN2022/100642
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English (en)
Chinese (zh)
Inventor
张会来
赵桂森
王先火
陈鑫
费越
俞尚哲
Original Assignee
天津医科大学肿瘤医院
山东大学
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Application filed by 天津医科大学肿瘤医院, 山东大学 filed Critical 天津医科大学肿瘤医院
Publication of WO2022268148A1 publication Critical patent/WO2022268148A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the invention relates to the field of organic compound synthesis and medical application, in particular to a compound for degrading BTK protein and its preparation method and application.
  • B-cell lymphoma is a kind of non-Hodgkin lymphoma (Non-Hodgkin lymphoma, NHL) with poor clinical curability and prognosis, and some malignant B-cell lymphomas are incurable (see Armitage, J.O.; Gascoyne, R.D.; Lunning, M.A.; Cavalli, F., Non-Hodgkin lymphoma. Lancet 2017, 390(10091), 298-310.).
  • the B cell receptor (BCR) signaling pathway is a specific pathway for the growth and survival of B cells, and its abnormal expression and overactivation are key factors in the occurrence of B cell lymphoma.
  • BTK Bacton's tyrosine kinase
  • IBN Ibrutinib
  • IBN is the first irreversible covalent BTK inhibitor launched in 2013. Although it has achieved good clinical efficacy, it is prone to drug resistance and side effects (see Liang, C.; Tian, D.
  • Ubiquitin-proteasome system (ubiquitin-proteasome system, UPS) is the main way to degrade ubiquitinated proteins in eukaryotic organisms. Protein degradation targeting chimera technology is an emerging technology that has developed rapidly in recent years.
  • target protein ubiquitin Proteolysis-targeting chimera (PROTACs) for targeted protein degradation and cancer therapy. J Hematol Oncol 2020,13(1),50.), can provide a new strategy for the treatment of B-cell lymphoma.
  • the object of the present invention is to provide a compound for degrading BTK protein and its preparation method and application.
  • the compound for degrading BTK protein can effectively degrade the BTK protein of lymphoma cells and inhibit the proliferation of tumor cells.
  • the technical solution of the present invention is as follows:
  • X is selected from methylene, pyrrolidinyl, benzyl, piperidinyl, pyridyl, pyrimidinyl, imidazolyl or oxadiazolyl; m is selected from 1-4; n is selected from 1-5.
  • piperidinyl when X is piperidinyl, piperidinyl is The carbon connection end of piperidinyl is connected with the nitrogen connection end of pyrazole; when X is pyrrolidinyl, pyrrolidinyl is The carbon connection end of pyrrolidinyl is connected with the nitrogen connection end of pyrazole; m is selected from 1, 2, 3, 4; n is selected from 1, 3, 4, 5.
  • a compound that degrades BTK protein according to the present invention has the following structure:
  • the method specifically includes the following steps: using 4-aminopyrazolo[3,4-d]pyrimidine, namely compound 1, as a starting material, in DMF with N-bromosuccinimide (NBS) through bromination Free radical reaction gives intermediate 2; intermediate 2 reacts with N-Boc-4-hydroxyl X or 1-Boc-3-hydroxyl X by Mitsunobu to give intermediate 3; intermediate 3 is in tetrahydrofuran/concentrated hydrochloric acid Remove the tert-butoxycarbonyl protecting group to obtain intermediate 4; intermediate 2 or 4 reacts with different bromine-substituted carboxylate methyl and ethyl esters to obtain intermediate 5 through nucleophilic substitution; intermediate 5 and 4-phenoxy Phenylboronic acid was catalyzed by tetrakis (triphenylphosphine) palladium, and intermediate 6 was obtained through Suzuki-Miyaura reaction; intermediate 6 was hydrolyzed under basic conditions to obtain intermediate 7; final intermediate 7 and intermediate
  • the third aspect of the present invention is a pharmaceutical composition, which comprises the BTK protein-degrading compound described in the first aspect above.
  • the fourth aspect of the present invention is a pharmaceutical preparation, which includes an active ingredient and a pharmaceutically acceptable adjuvant and/or carrier, and the active ingredient includes the above-mentioned BTK protein-degrading compound, or includes the above-mentioned pharmaceutical composition.
  • the application of the BTK protein-degrading compound described in the above-mentioned first aspect or the pharmaceutical composition described in the above-mentioned third aspect in the preparation of a BTK protein-degrading compound drug in the fifth aspect of the present invention, the application of the BTK protein-degrading compound described in the above-mentioned first aspect or the pharmaceutical composition described in the above-mentioned third aspect in the preparation of a BTK protein-degrading compound drug.
  • the application of a BTK protein-degrading compound described in the above-mentioned first aspect or the pharmaceutical composition described in the above-mentioned third aspect in the preparation of a drug for treating B-cell lymphoma in the seventh aspect of the present invention, the application of a BTK protein-degrading compound described in the above-mentioned first aspect or the pharmaceutical composition described in the above-mentioned third aspect in the preparation of a drug for treating B-cell lymphoma.
  • the compounds of the present invention have the effect of significantly degrading BTK protein on B cell lymphoma cells, wherein compounds I-6, I-7, I-8, I-10, I-11, I-14, I-15, I-16, I-17, I-18, I-21, I-23 and I-24 can effectively degrade BTK protein, especially compounds I-7, I-21 and I-23 on B-cell lymphoma cell beads Jeko-1 showed concentration-dependent and time-dependent significant degradation of BTK protein.
  • reagents or raw materials used in the present invention can be purchased through conventional channels. Unless otherwise specified, the reagents or raw materials used in the present invention are used in accordance with conventional methods in the art or according to product instructions. In addition, any methods and materials similar or equivalent to those described can be applied to the method of the present invention.
  • Embodiment 1 the preparation of intermediate 2
  • Embodiment 2 the preparation of intermediate 3
  • Embodiment 3 the preparation of intermediate 4
  • intermediate 3a-3b in a 250ml eggplant-shaped bottle, directly add 20mL of anhydrous THF and stir to dissolve, slowly add 5mL of concentrated hydrochloric acid into the eggplant-shaped bottle, and react at room temperature for 4 hours, a white solid precipitates, TLC detects that the reaction is complete, and directly suction filter , the filter cake was washed with ethyl acetate and dried to give intermediate 4a-4b.
  • Embodiment 4 the preparation of intermediate 5
  • Embodiment 6 the preparation of intermediate 7
  • Embodiment 7 the preparation of intermediate 10
  • Embodiment 8 the preparation of intermediate 11
  • Embodiment 9 the preparation of intermediate 12
  • Embodiment 10 the preparation of intermediate 13
  • Embodiment 11 the preparation of intermediate 14
  • reaction was detected by TLC, and the reaction solution was poured into a 150mL ice-water bath to precipitate a white solid, cooled to room temperature, filtered with suction, the filter cake was washed with cold water, and dried to obtain a white solid.
  • dichloromethane:methanol 100:1 ⁇ 60:1 ⁇ 20:1, to obtain the target final products I-1 to I-24.
  • Lymphoma cell lines Jeko-1, K562, HEL Cell Bank of Chinese Academy of Sciences
  • 1640 medium was purchased from Israel Biological Industries
  • PBS phosphate buffer (powder) was purchased from Beijing Dingguo Changsheng Biotechnology Co., Ltd.
  • penicillin-streptomycin mixed solution (100 ⁇ double antibody) was purchased from American Genview Company, poloxamer (F-127) was purchased from Amresco, cell proliferation and toxicity detection kit (Cell Counting Kit-8, CCK8 ) was purchased from Dalian Meilun Biotechnology Co., Ltd., fetal bovine serum (FBS) was purchased from Gibco Company of the United States, the refrigerated centrifuge was purchased from Eppendorf Company of Germany, the Infinite F50 absorbing optical microplate reader was purchased from Tecan Company of Austria, and the cell culture box was purchased from Japan Panasonic Corporation (Model: MCO-170AICUVL-PC).
  • FBS fetal bovine serum
  • Experimental method take the cells in the logarithmic growth phase, centrifuge at 1000rpm for 5min, discard the upper medium, and dilute the centrifuged cells with 1640 medium containing 20% FBS to form a uniform cell suspension, according to the number of cells 4 ⁇ 10 4 /well Calculate the required number of cells, inoculate the cell suspension in a 96-well culture plate at 100 ⁇ L/well, and set up a 100% cell control at the same time Add 100 ⁇ L of cell suspension and 100 ⁇ L of blank medium, blank control Add 200 ⁇ L blank medium. Then the medium of different concentrations of compounds ( F127 ⁇ 1 %) was added to the corresponding 96-well plate, and 4 replicate wells were set for each concentration. Incubate for 48h.
  • the half-inhibitory concentration (IC 50 value) of tumor cells the results showed that the IC 50 values of compound I-7, I-21, I-23 and I-24 inhibited Jeko-1 cells were 4.6 ⁇ M, 4.1 ⁇ M, 3.6 ⁇ M, respectively ⁇ M and 4.2 ⁇ M, the IC 50 value of the positive control drug IBN was 4.7 ⁇ M; the half-inhibitory concentration (IC 50 value) of compound I-21 and I-23 on K562 cells was 8 ⁇ M and 7 ⁇ M, respectively, and the IC 50 value of the positive control drug IBN The 50 value was 10 ⁇ M; the growth inhibitory effect of compounds I-21 and I-23 on HEL cells was twice that of the positive control drug IBN (IC 50 values were 16 ⁇ M, 15 ⁇ M and 31 ⁇ M, respectively).
  • Experimental example 14 Western blot experiment of the target compound on the B-cell lymphoma cell line Jeko-1
  • SDS-PAGE electrophoresis take gradient separation gel, take 20 ⁇ g protein samples for each group to load, and take protein markers to load at the same time.
  • Membrane transfer Soak the qualitative filter paper and PVDF membrane together in the electrophoresis solution; take out the electrophoresed glass plate separately, and then transfer the SDS-PAGE gel to the electrotransfer solution; sandwich the gel and PVDF between the filter paper and soak in the electrophoresis solution. In the electroporation fluid of the transfer device.
  • Blocking the membrane containing the target protein is placed in 5% skimmed milk powder solution to block non-specific binding.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Epidemiology (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne un composé permettant de dégrader une protéine BTK, son procédé de préparation et son utilisation. Le composé permettant de dégrader une protéine BTK a une structure représentée par la formule générale I. La présente invention concerne en outre une composition pharmaceutique contenant le composé ayant la structure représentée par la formule I. Les expériences d'activité de criblage montrent que le composé selon la présente invention peut dégrader de manière efficace une protéine BTK, et a un effet d'inhibition de la croissance sur des cellules de lymphome à cellules B. Par conséquent, la présente invention concerne en outre l'utilisation du composé dans la préparation d'un médicament antitumoral.
PCT/CN2022/100642 2021-06-24 2022-06-23 Composé pour dégrader la protéine btk, son procédé de préparation et son utilisation WO2022268148A1 (fr)

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CN202110708068.5A CN115521313B (zh) 2021-06-24 2021-06-24 一种降解btk蛋白的化合物及其制备方法和应用
CN202110708068.5 2021-06-24

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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN111662294A (zh) * 2019-03-05 2020-09-15 上海美志医药科技有限公司 一类具有降解Btk活性的化合物
CN112010858A (zh) * 2019-05-31 2020-12-01 四川海思科制药有限公司 一种btk抑制剂及其制备方法和药学上的应用
WO2020239103A1 (fr) * 2019-05-31 2020-12-03 四川海思科制药有限公司 Dérivé de cycle inhibiteur de btk, son procédé de préparation et son application pharmaceutique
WO2020252397A1 (fr) * 2019-06-12 2020-12-17 Baylor College Of Medicine Chimères ciblant la protéolyse à petites molécules et leurs méthodes d'utilisation
WO2020263935A1 (fr) * 2019-06-24 2020-12-30 Dana-Farber Cancer Institute, Inc. Agents de dégradation de hck et leurs utilisations

Family Cites Families (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DK3013337T3 (en) * 2013-06-26 2019-02-25 Abbvie Inc PRIMARY CARBOXAMIDES AS BTK INHIBITORS
CN109422752B (zh) * 2017-09-03 2023-04-07 上海美志医药科技有限公司 一类具有抑制并降解布鲁顿酪氨酸蛋白激酶Btk活性的化合物
US20200121684A1 (en) * 2018-03-10 2020-04-23 Yale University Modulators of btk proteolysis and methods of use
CN110835345A (zh) * 2018-08-17 2020-02-25 中国科学院上海药物研究所 一类细胞周期依赖性激酶的降解剂、其制备方法、药物组合物及其用途
CN109369654A (zh) * 2018-11-20 2019-02-22 山东大学 1，3-二取代-4-氨基吡唑并嘧啶类化合物及其制备方法和应用
CN110845500B (zh) * 2019-10-09 2021-05-11 清华大学 靶向btk降解化合物在治疗自身免疫系统疾病中的应用
CN111662296B (zh) * 2020-06-02 2021-12-31 山东大学 一种含吡唑并嘧啶的异羟肟酸衍生物及其制备方法和应用

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN111662294A (zh) * 2019-03-05 2020-09-15 上海美志医药科技有限公司 一类具有降解Btk活性的化合物
CN112010858A (zh) * 2019-05-31 2020-12-01 四川海思科制药有限公司 一种btk抑制剂及其制备方法和药学上的应用
WO2020239103A1 (fr) * 2019-05-31 2020-12-03 四川海思科制药有限公司 Dérivé de cycle inhibiteur de btk, son procédé de préparation et son application pharmaceutique
WO2020252397A1 (fr) * 2019-06-12 2020-12-17 Baylor College Of Medicine Chimères ciblant la protéolyse à petites molécules et leurs méthodes d'utilisation
WO2020263935A1 (fr) * 2019-06-24 2020-12-30 Dana-Farber Cancer Institute, Inc. Agents de dégradation de hck et leurs utilisations

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