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WO2021196655A1 - Composé contenant une structure benzimidazole, son procédé de préparation et application de celui-ci - Google Patents

Composé contenant une structure benzimidazole, son procédé de préparation et application de celui-ci Download PDF

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Publication number
WO2021196655A1
WO2021196655A1 PCT/CN2020/130051 CN2020130051W WO2021196655A1 WO 2021196655 A1 WO2021196655 A1 WO 2021196655A1 CN 2020130051 W CN2020130051 W CN 2020130051W WO 2021196655 A1 WO2021196655 A1 WO 2021196655A1
Authority
WO
WIPO (PCT)
Prior art keywords
arh
acid
compound
pharmaceutically acceptable
acceptable salt
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/CN2020/130051
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English (en)
Chinese (zh)
Inventor
朱启华
徐云根
施锦渝
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
China Pharmaceutical University
Jiangsu Tasly Diyi Pharmaceutical Co Ltd
Original Assignee
China Pharmaceutical University
Jiangsu Tasly Diyi Pharmaceutical Co Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from CN202010259262.5A external-priority patent/CN113493437B/zh
Application filed by China Pharmaceutical University, Jiangsu Tasly Diyi Pharmaceutical Co Ltd filed Critical China Pharmaceutical University
Publication of WO2021196655A1 publication Critical patent/WO2021196655A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4184—1,3-Diazoles condensed with carbocyclic rings, e.g. benzimidazoles
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • 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
    • 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
    • C07D401/12—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 linked by a chain containing hetero atoms as chain links

Definitions

  • the invention relates to the field of medicinal chemistry, and discloses a compound containing a benzimidazole structure and a preparation method and application thereof.
  • ROS1 as a new lung cancer driver gene, has become a clear lung cancer treatment target.
  • crizotinib has been successfully used in clinical trials of NSCLC for the treatment of ROS1 mutations, the current clinical results have found that, like most anti-tumor drugs, long-term application can easily lead to drug resistance.
  • crizotinib and entritinib are both non-specific ROS1 inhibitors, so far there is no highly selective ROS1 inhibitor. Therefore, it is of great practical significance to find specific ROS1 inhibitors with strong activity and high safety.
  • the present invention discloses a class of compounds containing a benzimidazole ring structure, and provides a specific preparation method of this class of compounds and their pharmaceutical applications as selective ROS1 inhibitors.
  • the present invention discloses a compound of general formula (I) or a pharmaceutically acceptable salt thereof:
  • R 1 represents H, COOH, COOR 4 or CONHR 4 , where R 4 represents hydrogen, C 1 ⁇ C 6 alkyl;
  • R 2 represents hydrogen, a C 1 ⁇ C 5 alkyl group
  • R 3 represents an optionally substituted benzene ring or aromatic heterocyclic ring, the aromatic heterocyclic ring is a six-membered or five-membered aromatic heterocyclic ring, the substituent is a halogen, a C 1 ⁇ C 3 alkyl, alkoxy, Halogenated alkyl, halogenated alkoxy, OH, NR 5 R 6 or CN, where R 5 and R 6 represent hydrogen, C 1 ⁇ C 6 alkyl;
  • R 1 represents H, COOH, COOR 4 or CONHR 4 , wherein R 4 represents hydrogen, C 1 ⁇ C 6 alkyl;
  • R 2 represents hydrogen, a C 1 ⁇ C 3 alkyl group
  • R 3 represents an optionally substituted benzene ring or aromatic heterocyclic ring, the aromatic heterocyclic ring is a six-membered or five-membered aromatic heterocyclic ring, and the substituents are F, Cl, Br, I, CH 3 , C 2 H 5 , OH, NR 5 R 6 , OCH 3 , OCF 3 , CF 3 or CN, where R 5 and R 6 represent hydrogen, C 1 ⁇ C 6 alkyl;
  • R 1 is more preferably CONH 2 or CONHCH 3 ;
  • R 3 is further preferably an optionally substituted phenyl group, and the substituent is preferably F, Cl, Br, CH 3 , OH, NH 2 , OCH 3 , OCF 3 or CF 3 .
  • R 1 is more preferably CONH 2 or CONHCH 3 ;
  • R 2 is more preferably CH 3 ,
  • R 3 is more preferably an optionally substituted phenyl group, and the substituents are F, CH 3 , CH 2 CH 3 , and OCH 3 .
  • the benzimidazole compound of the present invention is selected from I-1 to I-8:
  • R 1 , R 2 , and R 3 are the same as before;
  • Compound IV is prepared by reacting compound II with compound III, the base used is selected from sodium hydrogen, potassium carbonate, sodium carbonate, potassium tert-butoxide, sodium hydroxide, potassium hydroxide, sodium ethoxide, preferably sodium hydrogen; the solvent used is selected from N, N-dimethylformamide, N,N-dimethylacetamide, acetone, 1,4-dioxane, tetrahydrofuran, ethanol, acetonitrile, acetone, water or a mixed solvent composed of any two, preferably N, N-dimethylformamide;
  • Compound VI is prepared by reacting compound IV with compound V, the solvent used is selected from toluene, N,N-dimethylformamide, ethylene glycol dimethyl ether, 1,4-dioxane, tetrahydrofuran, ethanol, acetonitrile, acetone , Water or a mixed solvent composed of any two, preferably tetrahydrofuran/water; the base used is selected from sodium ethoxide, potassium acetate, sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate or triethylamine, preferably potassium carbonate; the catalyst used It is Pd(PPh 3 ) 4 , Pd(dppf)Cl 2 , Pd(PPh 3 ) 2 Cl 2 or Pd(OAc) 2 , preferably Pd(PPh 3 ) 4 .
  • the solvent used is selected from toluene, N,N-dimethylformamide, ethylene glycol dimethyl ether, 1,4-diox
  • Compound VII is prepared from compound VI through hydrolysis reaction, the base used is selected from lithium hydroxide, sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate, preferably sodium hydroxide; the solvent used is selected from water, methanol, ethanol, tetrahydrofuran or any A mixed solvent composed of the two is preferably methanol/water.
  • Compound IX is prepared by reacting compound VII with compound VIII.
  • the condensing agent used is selected from carbonyldiimidazole (CDI), dicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide (DIC), 1-(3).
  • HATU hexafluorophosphate benzotriazol-1-yl-oxytripyrrolidinyl phosphorus
  • PyBOP hexafluorophosphate benzotriazol-1-yl-oxytripyrrolidinyl phosphorus
  • the dehydrating agent is selected from glacial acetic acid, polyphosphoric acid, hydrochloric acid, acetic anhydride, preferably glacial acetic acid;
  • Compound IA is prepared by reduction reaction of compound IX, the solvent used is selected from methanol, ethanol, ethyl acetate, tetrahydrofuran, N,N-dimethylformamide, N,N-dimethylacetamide, 1,4-dioxide A mixed solvent composed of six rings, water or any two, preferably methanol/tetrahydrofuran; the reducing agent used is selected from iron powder/dilute hydrochloric acid, stannous chloride, sodium sulfide, palladium carbon, platinum carbon, Raney nickel, preferably palladium carbon ;
  • the present invention also discloses a pharmaceutical composition, which contains the compound of the above general formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.
  • the compounds can be added with pharmaceutically acceptable carriers to prepare common medicinal preparations, such as tablets, capsules, syrups, suspensions, injections, and can be added with flavors, sweeteners, liquid or solid fillers or diluents, etc. medical supplements.
  • the compound of the present invention can selectively inhibit ROS1, and can be used to prepare drugs for treating cancers such as non-small cell lung cancer.
  • the use of selective ROS1 inhibitors can reduce off-target effects, reduce toxic side effects, and improve treatment safety.
  • the reaction system was evaporated to remove the solvent under reduced pressure, and 10 mL ethyl acetate and 15 mL were added to separate the layers.
  • the aqueous phase was extracted with ethyl acetate once (10 mL).
  • the organic phases were combined and washed with saturated sodium chloride (10 mL). ⁇ 3), dried over anhydrous magnesium sulfate, filtered with suction, evaporated under reduced pressure to remove the solvent, and purified by column chromatography to obtain 0.44 g of light yellow solid, yield: 84.00%, mp 130-132°C.
  • the aqueous phase was collected, adjusted to pH 5 with 6 mol/L hydrochloric acid solution, extracted with ethyl acetate (10 mL ⁇ 2), dried with anhydrous magnesium sulfate, and filtered , The solvent was evaporated under reduced pressure to obtain 0.37 g of yellow solid, yield: 91.79%, mp 167-169°C.
  • reaction system was evaporated to remove the solvent under reduced pressure, 15 mL ethyl acetate and 20 mL were added to separate the layers, the aqueous phase was extracted with ethyl acetate once (15 mL), and the organic phases were combined and washed with saturated sodium chloride (15 mL ⁇ 3), dried over anhydrous magnesium sulfate, filtered with suction, evaporated under reduced pressure to remove the solvent, and purified by column chromatography to obtain 0.89 g of light yellow solid, yield: 86.08%, mp 103-106°C.
  • VI-6 (0.87 g, 2.53 mmol) was dissolved in 15 mL methanol and 55 mL water, 3 mL 20% sodium hydroxide solution was added, and the reaction was heated to 70° C. for 1 h. TLC detected that the raw material had reacted completely. The heating was stopped, the reaction system was cooled to room temperature, 30mL ethyl acetate was added for extraction, the aqueous phase was collected, adjusted to pH 5 with 6mol/L hydrochloric acid solution, extracted with ethyl acetate (30mL ⁇ 2), dried with anhydrous magnesium sulfate, filtered The solvent was evaporated under reduced pressure to obtain 0.65 g of light yellow solid, yield: 81.22%, mp 172-175°C.
  • Dissolve VI-7 (0.85 g, 2.45 mmol) in 15 mL methanol and 55 mL water, add 3 mL 20% sodium hydroxide solution, and heat to 70° C. to react for 1 hour. TLC detects that the raw material has reacted completely. The heating was stopped, the reaction system was cooled to room temperature, 30mL ethyl acetate was added for extraction, the aqueous phase was collected, adjusted to pH 5 with 6mol/L hydrochloric acid solution, extracted with ethyl acetate (30mL ⁇ 2), dried with anhydrous magnesium sulfate, filtered The solvent was evaporated under reduced pressure to obtain 0.71 g of yellow solid, yield: 91.10%, mp168-171°C.
  • VI-8 (1.13 g, 3.35 mmol) was dissolved in 15 mL methanol and 55 mL water, 3 mL 20% sodium hydroxide solution was added, and the reaction was heated to 70° C. for 1 h. TLC detected the complete reaction of the raw materials.
  • the Caliper Mobility Shift Assay method was used to detect the inhibitory effects of the compounds on the kinases ROS1, ALK and c-Met.
  • the compound test started with a concentration of 10 ⁇ M or 5 ⁇ M, and a 3-fold dilution of 7 or 8 concentrations.
  • a dispenser Echo 550 to transfer 250 nL of 100-fold final concentration compound to a 384-well reaction plate, add 10 ⁇ L of kinase solution with a final concentration of 1.25 nM ALK or 1.25 nM c-Met or 0.3 nM ROS1, and pre-incubate at room temperature for 10 minutes (negative
  • the control well contains 10 ⁇ L kinase buffer and 250 nL 100% DMSO; the positive control well contains 10 ⁇ L kinase solution and 250 nL 100% DMSO).
  • Add 15 ⁇ L of ATP with a final concentration of 30 ⁇ M and 3 ⁇ M substrate No.
  • negative control wells represent the conversion rate readings without enzyme active wells
  • Positive control wells represent the conversion rate readings of wells without compound inhibition.
  • IC 50 0.01 ⁇ 0.5 ⁇ M (denoted as: A); IC 50 : 0.5 ⁇ 5.0 ⁇ M (denoted as: B); IC 50 : >5.0 ⁇ M (denoted as: C).
  • Cell culture Resuspend the cells and count them with an automatic cell counter. According to the Ba/F3 seeding density, 2000 cells per well, the cell suspension is diluted to the required density. Pour 95 ⁇ L of cells in each well and incubate at 37°C for a stable equilibrium.
  • Compound preparation Dissolve the compound in DMSO, prepare a 20mM stock solution, and store at -20°C in the dark until use. After the cells are cultured, the compound is prepared into a diluted solution with a final concentration of 200 times. The compound was diluted with culture medium to prepare a compound of 20 times the final concentration. Add 5 ⁇ L of compound to each well, use the same volume of DMSO as the control, and incubate at 37° C., 5% CO 2 for 72 hours.
  • Cell detection equilibrate the cell plate to room temperature. Add 40 ⁇ L per well Reagent, shake for 2 minutes and let stand for 10 minutes. Use SpectraMax Paradigm to detect.
  • IC 50 :10.0 ⁇ 100.0nM (denoted as: A); IC 50 : 100.0 ⁇ 1000.0nM (denoted as: B); IC 50 :>1000nM (denoted as: C).

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

Abstract

L'invention concerne le domaine de la chimie pharmaceutique et concerne un composé contenant une structure benzimidazole, son procédé de préparation et une application de celui-ci. L'invention concerne un composé représenté par la formule générale (I), ou un sel pharmaceutiquement acceptable de celui-ci. R1 représente H, COOH, COOR4 ou CONHR4, où R4 représente hydrogène ou un groupe alkyle en C1-C6, R2 représente hydrogène ou un groupe alkyle en C1-C5, et R3 représente un noyau benzénique éventuellement substitué ou un noyau hétérocyclique aromatique. Le noyau hétérocyclique aromatique est un noyau hétérocyclique aromatique à six chaînons ou à cinq chaînons. Le substituant est halogène, alkyle en C1-C3, alcoxy, haloalkyle, haloalcoxy, OH, NR5R6 ou CN, où R5 et R6 représentent hydrogène ou un groupe alkyle en C1-C6. Le composé selon la présente invention peut être utilisé pour traiter des tumeurs.
PCT/CN2020/130051 2020-04-03 2020-11-19 Composé contenant une structure benzimidazole, son procédé de préparation et application de celui-ci Ceased WO2021196655A1 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
CN202010259262.5 2020-04-03
CN202010259262.5A CN113493437B (zh) 2020-04-03 2020-04-03 含苯并咪唑结构的化合物及其制备方法和用途
CN202011260117 2020-11-12
CN202011260117.5 2020-11-12

Publications (1)

Publication Number Publication Date
WO2021196655A1 true WO2021196655A1 (fr) 2021-10-07

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006021884A2 (fr) * 2004-08-26 2006-03-02 Pfizer Inc. Composes d'aminoheteroaryle enantiomeriquement purs utilises comme inhibiteurs de proteine kinase
CN103265477A (zh) * 2003-02-26 2013-08-28 苏根公司 作为蛋白激酶抑制剂的氨基杂芳基化合物
CN103841972A (zh) * 2011-08-02 2014-06-04 辉瑞公司 用于癌症的治疗的克里唑蒂尼

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103265477A (zh) * 2003-02-26 2013-08-28 苏根公司 作为蛋白激酶抑制剂的氨基杂芳基化合物
WO2006021884A2 (fr) * 2004-08-26 2006-03-02 Pfizer Inc. Composes d'aminoheteroaryle enantiomeriquement purs utilises comme inhibiteurs de proteine kinase
CN103841972A (zh) * 2011-08-02 2014-06-04 辉瑞公司 用于癌症的治疗的克里唑蒂尼

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