WO2024109642A1 - UTILISATION D'UN COMPOSÉ BENZOAZACYCLIQUE EN TANT QUE MODULATEUR ALLOSTÉRIQUE D'UN β2-ADRÉNORÉCEPTEUR - Google Patents

UTILISATION D'UN COMPOSÉ BENZOAZACYCLIQUE EN TANT QUE MODULATEUR ALLOSTÉRIQUE D'UN β2-ADRÉNORÉCEPTEUR Download PDF

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WO2024109642A1
WO2024109642A1 PCT/CN2023/132226 CN2023132226W WO2024109642A1 WO 2024109642 A1 WO2024109642 A1 WO 2024109642A1 CN 2023132226 W CN2023132226 W CN 2023132226W WO 2024109642 A1 WO2024109642 A1 WO 2024109642A1
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compound
nmr
phenyl
dmso
mhz
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PCT/CN2023/132226
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Chinese (zh)
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陈新
钱明成
赵帅
侯亚男
李晴
雒智杰
戚颖
黑晓源
李湖进
李燕
洪美龄
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常州大学
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Priority claimed from CN202310937574.0A external-priority patent/CN116874432A/zh
Priority claimed from CN202311189427.6A external-priority patent/CN117229217A/zh
Priority claimed from CN202311215367.0A external-priority patent/CN117447381A/zh
Application filed by 常州大学 filed Critical 常州大学
Publication of WO2024109642A1 publication Critical patent/WO2024109642A1/fr

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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
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • 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
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • 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
    • A61P9/06—Antiarrhythmics
    • 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
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
    • C07D209/42—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/54—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings condensed with carbocyclic rings or ring systems
    • C07D231/56—Benzopyrazoles; Hydrogenated benzopyrazoles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
    • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
    • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
    • C07D235/24—Benzimidazoles; Hydrogenated benzimidazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 2

Definitions

  • the invention belongs to the field of medicinal chemistry, and specifically discloses the application of a benzazazepine heterocyclic compound as a ⁇ 2 -adrenergic receptor ( ⁇ 2 -AR ) allosteric modulator.
  • G protein-coupled receptors are the largest gene family in the human genome, with more than 800 members. GPCRs are closely related to a wide range of physiological functions, including development, immunity, hormone regulation, and neuronal activity. Typically, GPCRs convert extracellular stimuli into intracellular responses by activating heterotrimeric G proteins composed of Ga, Gb, and Gg subunits. (Cell Reports 2023, 42: 113173).
  • GPCRs signals are transmitted through two pathways: G protein-dependent and G protein-independent, producing different biological effects (Journal of Medicinal Chemistry 2018, 61(22): 9841-9878.).
  • the former often involves the activation of G proteins, while the latter often triggers the recruitment of arrestins proteins.
  • GPCRs G-protein-coupled receptors
  • ⁇ 2 -AR antagonists are very classic GPCRs drugs, playing an important role in the treatment of diseases such as heart failure, hypertension, coronary heart disease, arrhythmia, angina pectoris, etc., and are the cornerstone of the treatment of cardiovascular diseases. Therefore, the development and design of ⁇ 2 -AR allosteric antagonists are of great significance for the treatment of various cardiovascular diseases.
  • Cmpd-15 small molecule negative allosteric modulator compound 15
  • ⁇ 2 -AR the first intracellular allosteric antagonist of ⁇ 2 -AR
  • the present invention uses various substituted 3-carboxylic acid benzazazepines and various amines as raw materials, and synthesizes a series of various substituted benzopyrazole amides, benzimidazole amides and indole amide derivatives through amide coupling reaction.
  • the GloSensor cAMP accumulation experiment confirms that most of the synthesized compounds are allosteric antagonists of ⁇ 2 -AR, and the activity of some of the compounds is significantly higher than that of the lead compound Cmpd-15.
  • the present invention may provide a solid foundation for the creation of new drugs for cardiovascular, asthma and cancer diseases.
  • the present invention provides a benzene nitrogen heterocyclic compound, the structural formula of the benzene nitrogen heterocyclic compound is as follows:
  • R 1 H, methyl, methoxy, phenyl, F, Cl, Br, I, CN, NO 2 , NH 2 , OH, CF 3 ;
  • R 2 H, methyl, phenyl, benzyl
  • R 3 H, alkyl
  • R 4 H, alkyl, cycloalkyl, phenyl, substituted phenyl, substituted benzyl.
  • benzazine heterocyclic compound is a benzimidazole amide compound, and its general structural formula is shown in Formula I:
  • R 1 is H, methyl, methoxy, phenyl, F, Cl, Br, I, CN, NO 2 , NH 2 , OH, CF 3 ;
  • R 3 is H, alkyl;
  • R 4 is H, phenyl, bromophenyl, fluorophenyl.
  • benzazine heterocyclic compound is a benzopyrazole amide compound, and its general structural formula is shown in Formula II:
  • R 1 is H, methyl, methoxy, phenyl, F, Cl, Br, I, CN, NO 2 , NH 2 , OH, CF 3 ;
  • R 2 is H, methyl, methoxy, phenyl, benzyl;
  • R 3 is H, alkyl;
  • R 4 is H, phenyl, bromophenyl, fluorophenyl.
  • benzazine heterocyclic compound is an indoleamide compound, and its general structural formula is shown in Formula III:
  • R 1 is H, methyl, methoxy, phenyl, F, Cl, Br, I, CN, NO 2 , NH 2 , OH, CF 3 ;
  • R 3 is H, alkyl;
  • R 4 is H, phenyl, bromophenyl, fluorophenyl.
  • the benzazazepine heterocyclic compound is an allosteric modulator of ⁇ 2 -adrenergic receptor ( ⁇ 2 -AR ).
  • the present invention also provides a method for synthesizing the above-mentioned benzazazepine heterocyclic compound, which specifically comprises the following steps: a simple amide coupling reaction is carried out between 3-carboxylic acid benzazazepine and various amines, firstly dissolving 3-carboxylic acid benzazazepine and an activator in a solvent, adding different types of amines under ice bath, then adding an acid binding agent and an amide coupling agent and continuing to stir to room temperature; the activator is 1-hydroxy-7-azabenzotriazole (HOAT), the acid binding agent is N-methylmorpholine (NMM), and the amide coupling agent is 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI); the molar ratio of 3-carboxylic acid benzazazepine: HOAT: amine: NMM: EDCI is 1:1.2-1.5:1-2:0.6-0.75:1.2-1.5.
  • Dissolve benzimidazole acid and activator in solvent add different types of amines under ice bath, then add acid binder and amide coupling agent and continue stirring to room temperature.
  • the solvent is N,N-dimethylformamide
  • the activator is 1-hydroxy-7-azabenzotriazole (HOAT)
  • the acid binder is N-methylmorpholine (NMM)
  • the amide coupling agent is 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride (EDCI).
  • Dissolve benzimidazole acid (1eq) and HOAT (1.2eq) in DMF stir for 10min, and add different amines.
  • Indolecarboxylic acid was dissolved in N,N-dimethylformamide (DMF) in a round-bottom flask, N-hydroxy-7-azabenzotriazole (HOAT) was added and reacted for 10 minutes, then amine and N-methylmorpholine (NMM) were added under ice bath conditions and reacted for 10 minutes, and then 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCl) was added and reacted at room temperature for 4 hours.
  • DMF N,N-dimethylformamide
  • HOAT N-hydroxy-7-azabenzotriazole
  • NMM N-methylmorpholine
  • EDCl 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride
  • the benzazazepine heterocyclic compound of the present invention is used for preparing beta 2 -adrenaline receptor allosteric antagonist.
  • benzopyrazole amide compounds are a new type of allosteric antagonist of ⁇ 2 -AR, and some of the compounds have significantly higher activity than the lead compound Cmpd-15. Moreover, these compounds have simple structures and can be obtained by only one organic reaction.
  • the present invention may provide a solid foundation for the creation of new drugs for cardiovascular, asthma and cancer diseases.
  • FIG1 is a graph showing a dose-response curve of ISO mediated by benzimidazole amide derivative A08;
  • FIG2 is a graph showing the ISO dose-response curve mediated by the benzopyrazole amide derivative B08;
  • FIG3 is a graph showing the ISO dose-response curve mediated by the indoleamide derivative C01;
  • FIG4 is a graph showing a dose-response curve of ISO mediated by indoleamide derivative C15;
  • FIG5 is a graph showing the ISO dose-response curve mediated by the indoleamide derivative C17.
  • Embodiment 1 is a diagrammatic representation of Embodiment 1:
  • Step 1 Dissolve 4-methylbenzene-1,2-diamine (1 g, 8.2 mmol) and glycolic acid (2.5 g, 32.8 mmol) in 6N HCl (41 mL) under ice bath, and stir under reflux at 120 ° C for 12 h. After the reaction, cool to room temperature, add concentrated ammonia water under ice bath to adjust pH to neutral, filter, and wash with water to obtain a pink solid compound (1.1 g, yield 79%).
  • Step 3 Dissolve 5-methyl-1H-benzimidazole-2-carboxylic acid (200 mg, 1.13 mmol) and HOAT (185 mg, 1.36 mmol) in DMF (6 mL), stir for 10 min, add compound methylamine hydrochloride (154 mg, 2.26 mmol), add N-methylmorpholine (0.092 mL, 0.79 mmol) under ice bath and stir for 10 min, add EDCI (261 mg, 1.36 mmol), keep stirring at 0 ° C for 1 h, and react at room temperature for 12 h.
  • Embodiment 2 is a diagrammatic representation of Embodiment 1:
  • Embodiment 3 is a diagrammatic representation of Embodiment 3
  • the preparation method is the same as that of Example 1, except that 4-methoxybenzene-1,2-diamine is used instead of 4-methylbenzene-1,2-diamine in step 1, and cyclopentylamine is used instead of methylamine hydrochloride in step 3 to obtain a white solid with a yield of 65%.
  • Embodiment 4 is a diagrammatic representation of Embodiment 4:
  • Embodiment 5 is a diagrammatic representation of Embodiment 5:
  • the preparation method is the same as that of Example 1, except that 4-methoxybenzene-1,2-diamine is used instead of 4-methylbenzene-1,2-diamine in step 1, and cyclohexylamine is used instead of methylamine hydrochloride in step 3, and the yield is 62%.
  • Embodiment 6 is a diagrammatic representation of Embodiment 6
  • the preparation method is the same as that of Example 1, except that benzene-1,2-diamine is used instead of 4-methylbenzene-1,2-diamine in step 1, and aniline is used instead of methylamine hydrochloride in step 3 to obtain a white solid with a yield of 55%.
  • Embodiment 7 is a diagrammatic representation of Embodiment 7:
  • Embodiment 8 is a diagrammatic representation of Embodiment 8
  • Embodiment 9 is a diagrammatic representation of Embodiment 9:
  • the preparation method is the same as that of Example 1, except that 4-fluoro-1,2-diamine is used instead of 4-methylbenzene-1,2-diamine in step 1, and aniline is used instead of methylamine hydrochloride in step 3 to obtain a white solid with a yield of 52%.
  • Embodiment 10 is a diagrammatic representation of Embodiment 10:
  • the preparation method is the same as that of Example 1, except that 4-chloro-1,2-diamine is used instead of 4-methylbenzene-1,2-diamine in step 1, and aniline is used instead of methylamine hydrochloride in step 3 to obtain a white solid with a yield of 52%.
  • Embodiment 11 is a diagrammatic representation of Embodiment 11:
  • the preparation method is the same as that of Example 1, except that 4-bromo-1,2-diamine is used instead of 4-methylbenzene-1,2-diamine in step 1, and aniline is used instead of methylamine hydrochloride in step 3 to obtain a white solid with a yield of 55%.
  • Embodiment 12 is a diagrammatic representation of Embodiment 12
  • the preparation method is the same as that of Example 1, except that 4-nitrobenzene-1,2-diamine is used instead of 4-methylbenzene-1,2-diamine in step 1, and aniline is used instead of methylamine hydrochloride in step 3 to obtain a white solid with a yield of 52%.
  • Embodiment 13 is a diagrammatic representation of Embodiment 13:
  • the preparation method is the same as that of Example 1, except that benzene-1,2-diamine is used instead of 4-methylbenzene-1,2-diamine in step 1, and m-bromoaniline is used instead of methylamine hydrochloride in step 3 to obtain a white solid with a yield of 52%.
  • Embodiment 14 is a diagrammatic representation of Embodiment 14:
  • the preparation method is the same as that of Example 1, except that 4-methylbenzene-1,2-diamine is used instead of 4-methylbenzene-1,2-diamine in step 1, and m-bromoaniline is used instead of methylamine hydrochloride in step 3 to obtain a white solid with a yield of 52%.
  • Embodiment 15 is a diagrammatic representation of Embodiment 15:
  • the preparation method is the same as that of Example 1, except that 4-methoxybenzene-1,2-diamine is used in place of 4-methylbenzene-1,2-diamine in step 1, and m-bromoaniline is used in place of methylamine hydrochloride in step 3 to obtain a white solid with a yield of 52%.
  • Embodiment 16 is a diagrammatic representation of Embodiment 16:
  • the preparation method is the same as that of Example 1, except that 4-fluoro-1,2-diamine is used instead of 4-methylbenzene-1,2-diamine in step 1, and m-bromoaniline is used instead of methylamine hydrochloride in step 3 to obtain a white solid with a yield of 52%.
  • Embodiment 17 is a diagrammatic representation of Embodiment 17:
  • the preparation method is the same as that of Example 1, except that 4-chloro-1,2-diamine is used instead of 4-methylbenzene-1,2-diamine in step 1, and m-bromoaniline is used instead of methylamine hydrochloride in step 3 to obtain a white solid with a yield of 52%.
  • Embodiment 18 is a diagrammatic representation of Embodiment 18:
  • the preparation method is the same as that of Example 1, except that 4-bromo-1,2-diamine is used instead of 4-methylbenzene-1,2-diamine in step 1, and m-bromoaniline is used instead of methylamine hydrochloride in step 3 to obtain a white solid with a yield of 52%.
  • 1 H NMR 400MHz, DMSO-d 6 ): ⁇ 13.70 (s, 1H), 11.21 (s, 1H), 7.94-7.91 (m, 2H), 7.55 (s, 1H), 7.34-7.32 (m, 2H).
  • Embodiment 19 is a diagrammatic representation of Embodiment 19:
  • the preparation method is the same as that of Example 1, except that 4-nitro-1,2-diamine is used instead of 4-methylbenzene-1,2-diamine in step 1, and m-bromoaniline is used instead of methylamine hydrochloride in step 3 to obtain a white solid with a yield of 52%.
  • 1 H NMR 400MHz, DMSO-d 6 ): ⁇ 14.12 (s, 1H), 11.30 (s, 1H), 8.51 (s, 1H), 8.22-8.19 (m, 2H), 7.94-7.80 (m, 2H), 7.36-7.33 (m, 2H).
  • Embodiment 20 is a diagrammatic representation of Embodiment 20.
  • the preparation method is the same as that of Example 1, except that 4-methyl-1,2-diamine is used instead of 4-methylbenzene-1,2-diamine in step 1, and m-bromobenzylamine is used instead of methylamine hydrochloride in step 3 to obtain a white solid with a yield of 52%.
  • Embodiment 21 is a diagrammatic representation of Embodiment 21.
  • the preparation method is the same as that of Example 1, except that 4-methoxy-1,2-diamine is used instead of 4-methylbenzene-1,2-diamine in step 1, and m-bromobenzylamine is used instead of methylamine hydrochloride in step 3 to obtain a white solid with a yield of 52%.
  • 1 H NMR 400MHz, DMSO-d 6 ): ⁇ 13.15 (s, 1H), 9.52 (s, 1H), 7.59-6.90 (m, 7H), 4.49 (s, 2H), 3.79 (s, 3H).
  • Embodiment 22 is a diagrammatic representation of Embodiment 22.
  • the preparation method is the same as that of Example 1, except that 4-fluoro-1,2-diamine is used instead of 4-methylbenzene-1,2-diamine in step 1, and m-bromobenzylamine is used instead of methylamine hydrochloride in step 3 to obtain a white solid with a yield of 52%.
  • Embodiment 23 is a diagrammatic representation of Embodiment 23.
  • the preparation method is the same as that of Example 1, except that 4-chloro-1,2-diamine is used instead of 4-methylbenzene-1,2-diamine in step 1, and m-bromobenzylamine is used instead of methylamine hydrochloride in step 3 to obtain a white solid with a yield of 52%.
  • Embodiment 24 is a diagrammatic representation of Embodiment 24.
  • the preparation method is the same as that of Example 1, except that 4-bromo-1,2-diamine is used instead of 4-methylbenzene-1,2-diamine in step 1, and m-bromobenzylamine is used instead of methylamine hydrochloride in step 3 to obtain a white solid with a yield of 52%.
  • Embodiment 25 is a diagrammatic representation of Embodiment 25.
  • the preparation method is the same as that of Example 1, except that 4-nitro-1,2-diamine is used instead of 4-methylbenzene-1,2-diamine in step 1, and m-bromobenzylamine is used instead of methylamine hydrochloride in step 3 to obtain a white solid with a yield of 52%.
  • Embodiment 26 is a diagrammatic representation of Embodiment 26.
  • the preparation method is the same as that of Example 1, except that 4-methyl-1,2-diamine is used instead of 4-methylbenzene-1,2-diamine in step 1, and m-fluoroaniline is used instead of methylamine hydrochloride in step 3 to obtain a white solid with a yield of 52%.
  • Embodiment 27 is a diagrammatic representation of Embodiment 27.
  • the preparation method is the same as that of Example 1, except that 4-methoxy-1,2-diamine is used instead of 4-methylbenzene-1,2-diamine in step 1, and m-fluoroaniline is used instead of methylamine hydrochloride in step 3 to obtain a white solid with a yield of 52%.
  • Embodiment 28 is a diagrammatic representation of Embodiment 28:
  • the preparation method is the same as that of Example 1, except that 4-methyl-1,2-diamine is used instead of 4-methylbenzene-1,2-diamine in step 1, and m-chloroaniline is used instead of methylamine hydrochloride in step 3 to obtain a white solid with a yield of 52%.
  • Embodiment 29 is a diagrammatic representation of Embodiment 29.
  • the preparation method is the same as that of Example 1, except that 4-chloromethoxy-1,2-diamine is used instead of 4-methylbenzene-1,2-diamine in step 1, and m-chloroaniline is used instead of methylamine hydrochloride in step 3 to obtain a white solid with a yield of 52%.
  • Embodiment 30 is a diagrammatic representation of Embodiment 30.
  • the preparation method is the same as that of Example 1, except that 4-methyl-1,2-diamine is used instead of 4-methylbenzene-1,2-diamine in step 1, and 3,5-dibromoaniline is used instead of methylamine hydrochloride in step 3 to obtain a white solid with a yield of 52%.
  • Embodiment 31 is a diagrammatic representation of Embodiment 31.
  • the preparation method is the same as that of Example 1, except that 4-methoxy-1,2-diamine is used instead of 4-methylbenzene-1,2-diamine in step 1, and 3,5-dibromoaniline is used instead of methylamine hydrochloride in step 3 to obtain a white solid with a yield of 52%.
  • Embodiment 32 is a diagrammatic representation of Embodiment 32.
  • N-phenylindazole-3-carboxylic acid was added to N,N-dimethylformamide (2 ml), and then 51.4 mg (0.2 mmol, 1 eq) of 2-amino-3-(3-bromophenyl)-N-methylpropionamide and 41 mg (0.3 mmol, 1.5 eq) of N-hydroxy-7-azabenzotriazole were added.
  • N-methylmorpholine (18 ⁇ L, 0.15 mmol, 0.75 eq) was added at 0 °C.
  • Embodiment 33 is a diagrammatic representation of Embodiment 33.
  • Embodiment 34 is a diagrammatic representation of Embodiment 34.
  • the preparation method is the same as that of Example 32, except that 2-amino-3-(3-bromophenyl)-N-methylpropionamide is replaced by m-chloroaniline, and compound B3 is finally obtained as a white solid with a yield of 67%.
  • Embodiment 35 is a diagrammatic representation of Embodiment 35.
  • Embodiment 36 is a diagrammatic representation of Embodiment 36.
  • the preparation method is the same as that of Example 32, except that N-phenylindazole-3-carboxylic acid is replaced by N-benzylindazole-3-carboxylic acid, and compound B5 is finally obtained as a white solid with a yield of 68%.
  • Embodiment 37 is a diagrammatic representation of Embodiment 37.
  • the preparation method is the same as that of Example 32, except that N-phenylindazole-3-carboxylic acid is replaced by N-methylindazole-3-carboxylic acid, and 2-amino-3-(3-bromophenyl)-N-methylpropionamide is replaced by m-bromoaniline, and compound B6 is finally obtained as a white solid with a yield of 90%.
  • Embodiment 38 is a diagrammatic representation of Embodiment 38.
  • Embodiment 39 is a diagrammatic representation of Embodiment 39.
  • the preparation method is the same as that of Example 32, except that N-phenylindazole-3-carboxylic acid is replaced by indazole-3-carboxylic acid, and 2-amino-3-(3-bromophenyl)-N-methylpropionamide is replaced by m-bromoaniline, to finally obtain compound B8 as a white solid with a yield of 78%.
  • Embodiment 40 is a diagrammatic representation of Embodiment 40.
  • the preparation method is the same as that of Example 32, except that N-phenylindazole-3-carboxylic acid is replaced by indazole-3-carboxylic acid, and 2-amino-3-(3-bromophenyl)-N-methylpropionamide is replaced by m-fluoroaniline, to finally obtain compound B9 as a white solid with a yield of 63%.
  • Embodiment 41 is a diagrammatic representation of Embodiment 41.
  • the preparation method is the same as that of Example 32, except that N-phenylindazole-3-carboxylic acid is replaced by indazole-3-carboxylic acid, and 2-amino-3-(3-bromophenyl)-N-methylpropionamide is replaced by m-chloroaniline, to finally obtain compound B10 as a white solid with a yield of 36%.
  • Embodiment 42 is a diagrammatic representation of Embodiment 42.
  • the preparation method is the same as that of Example 32, except that N-phenylindazole-3-carboxylic acid is replaced by indazole-3-carboxylic acid, and 2-amino-3-(3-bromophenyl)-N-methylpropionamide is replaced by m-methylaniline, to finally obtain compound B11 as a light yellow solid with a yield of 76%.
  • Embodiment 43 is a diagrammatic representation of Embodiment 43.
  • the preparation method is the same as that of Example 32, except that N-phenylindazole-3-carboxylic acid is replaced by indazole-3-carboxylic acid, and 2-amino-3-(3-bromophenyl)-N-methylpropionamide is replaced by 3,5-dibromoaniline, to finally obtain compound B12 as a white solid with a yield of 9%.
  • Embodiment 44 is a diagrammatic representation of Embodiment 44.
  • the preparation method is the same as that of Example 32, except that N-phenylindazole-3-carboxylic acid is replaced by indazole-3-carboxylic acid, and 2-amino-3-(3-bromophenyl)-N-methylpropionamide is replaced by benzylamine, to finally obtain compound B13 as a white solid with a yield of 93%.
  • Embodiment 45 is a diagrammatic representation of Embodiment 45.
  • the preparation method is the same as that of Example 32, except that N-phenylindazole-3-carboxylic acid is replaced by indazole-3-carboxylic acid, and 2-amino-3-(3-bromophenyl)-N-methylpropionamide is replaced by methylamine, to finally obtain compound B14 as a white solid with a yield of 86%.
  • Embodiment 46 is a diagrammatic representation of Embodiment 46.
  • the preparation method is the same as that of Example 32, except that N-phenylindazole-3-carboxylic acid is replaced by indazole-3-carboxylic acid, and 2-amino-3-(3-bromophenyl)-N-methylpropionamide is replaced by isopropylamine, to finally obtain compound B15 as a white solid with a yield of 83%.
  • Embodiment 47 is a diagrammatic representation of Embodiment 47.
  • the preparation method is the same as that of Example 32, except that N-phenylindazole-3-carboxylic acid is replaced by indazole-3-carboxylic acid, and 2-amino-3-(3-bromophenyl)-N-methylpropionamide is replaced by cyclohexylamine, to finally obtain compound B16 as a white solid with a yield of 81%.
  • Embodiment 48 is a diagrammatic representation of Embodiment 48.
  • the preparation method is the same as that of Example 32, except that N-phenylindazole-3-carboxylic acid is replaced by 5-bromoindazole-3-carboxylic acid, and 2-amino-3-(3-bromophenyl)-N-methylpropionamide is replaced by m-bromoaniline, and compound B17 is finally obtained as a white solid with a yield of 36%.
  • Embodiment 49 is a diagrammatic representation of Embodiment 49.
  • the preparation method is the same as that of Example 32, except that N-phenylindazole-3-carboxylic acid is replaced by 5-bromoindazole-3-carboxylic acid, and 2-amino-3-(3-bromophenyl)-N-methylpropionamide is replaced by aniline, to finally obtain compound B18 as a white solid with a yield of 44%.
  • Embodiment 50 is a diagrammatic representation of Embodiment 50.
  • the preparation method is the same as that of Example 32, except that N-phenylindazole-3-carboxylic acid is replaced by 5-methylindazole-3-carboxylic acid, and 2-amino-3-(3-bromophenyl)-N-methylpropionamide is replaced by aniline, and compound B19 is finally obtained as a yellow solid with a yield of 80%.
  • Embodiment 51 is a diagrammatic representation of Embodiment 51.
  • the preparation method is the same as that of Example 32, except that N-phenylindazole-3-carboxylic acid is replaced by 6-bromoindazole-3-carboxylic acid, and 2-amino-3-(3-bromophenyl)-N-methylpropionamide is replaced by aniline, to finally obtain compound B20 as a white solid with a yield of 83%.
  • Embodiment 52 is a diagrammatic representation of Embodiment 52.
  • Embodiment 53 is a diagrammatic representation of Embodiment 53.
  • Embodiment 54 is a diagrammatic representation of Embodiment 54:
  • Embodiment 55 is a diagrammatic representation of Embodiment 55:
  • Embodiment 56 is a diagrammatic representation of Embodiment 56.
  • Embodiment 57
  • Embodiment 58
  • Embodiment 59 is a diagrammatic representation of Embodiment 59.
  • Embodiment 60 is a diagrammatic representation of Embodiment 60.
  • Embodiment 62
  • Embodiment 63
  • Embodiment 64 is a diagrammatic representation of Embodiment 64.
  • the preparation method is the same as that of Example 53, except that 6-bromo-1H-indole-3-carboxylic acid is replaced by indole-3-carboxylic acid, and aniline is replaced by 3-bromoaniline, to finally obtain compound C 12 as a white solid with a yield of 51%.
  • Embodiment 65 is a diagrammatic representation of Embodiment 65.
  • the preparation method is the same as that of Example 32, except that 6-bromo-1H-indole-3-carboxylic acid is replaced by indole-3-carboxylic acid, and compound C 13 is finally obtained as a white solid with a yield of 8%.
  • Embodiment 66
  • the preparation method is the same as that of Example 53, except that 6-bromo-1H-indole-3-carboxylic acid is replaced by 6-fluoro-1H-indole-3-carboxylic acid, and aniline is replaced by 3-bromoaniline, to finally obtain compound C 14 as a light yellow solid with a yield of 17%.
  • Embodiment 67 is a diagrammatic representation of Embodiment 67.
  • the preparation method is the same as that of Example 53, except that 6-bromo-1H-indole-3-carboxylic acid is replaced by 6-fluoro-1H-indole-3-carboxylic acid, and compound C 15 is finally obtained as a light yellow solid with a yield of 70%.
  • Embodiment 68
  • the preparation method is the same as that of Example 32, except that 6-bromo-1H-indole-3-carboxylic acid is replaced by 6-chloroindole-3-carboxylic acid, and compound C 16 is finally obtained as a light yellow solid with a yield of 9%.
  • Embodiment 69
  • the preparation method is the same as that of Example 53, except that 6-bromo-1H-indole-3-carboxylic acid is replaced by 6-cyanoindole-3-carboxylic acid, and compound C 17 is finally obtained as a white solid with a yield of 6%.
  • Embodiment 70 is a diagrammatic representation of Embodiment 70.
  • the preparation method is the same as that of Example 53, except that 6-bromo-1H-indole-3-carboxylic acid is replaced by 5-fluoro-1H-indole-3-carboxylic acid, to finally obtain compound C 18 as light green solid particles with a yield of 10%.
  • Embodiment 71
  • the preparation method is the same as that of Example 53, except that 6-bromo-1H-indole-3-carboxylic acid is replaced by 6-bromoindole-2-carboxylic acid, to finally obtain compound D 01 as a light yellow solid with a yield of 68%.
  • Embodiment 72 is a diagrammatic representation of Embodiment 72.
  • the preparation method is the same as that of Example 53, except that 6-bromo-1H-indole-3-carboxylic acid is replaced by 6-bromoindole-2-carboxylic acid, and aniline is replaced by benzylamine, to finally obtain compound D 02 as a light yellow powder with a yield of 36%.
  • Embodiment 73
  • the preparation method is the same as that of Example 53, except that 6-bromo-1H-indole-3-carboxylic acid is replaced by 6-bromoindole-2-carboxylic acid, and aniline is replaced by 3-bromoaniline, to finally obtain compound D 03 as a white solid with a yield of 61%.
  • Embodiment 74
  • the preparation method is the same as that of Example 53, except that 6-bromo-1H-indole-3-carboxylic acid is replaced by 6-bromoindole-2-carboxylic acid, and aniline is replaced by 3-bromobenzylamine, to finally obtain compound D 04 as a light yellow solid with a yield of 80%.
  • Embodiment 75 is a diagrammatic representation of Embodiment 75.
  • the preparation method is the same as that of Example 53, except that 6-bromo-1H-indole-3-carboxylic acid is replaced by 6-bromoindole-2-carboxylic acid, and aniline is replaced by 3-fluoroaniline, to finally obtain compound D 05 as a light yellow solid with a yield of 66%.
  • Embodiment 76
  • the preparation method is the same as that of Example 53, except that 6-bromo-1H-indole-3-carboxylic acid is replaced by 6-bromoindole-2-carboxylic acid, and aniline is replaced by 3-chloroaniline, to finally obtain compound D 06 as a light yellow solid with a yield of 79%.
  • Embodiment 77
  • Embodiment 78
  • the preparation method is the same as that of Example 53, except that 6-bromo-1H-indole-3-carboxylic acid is replaced by 6-bromoindole-2-carboxylic acid, and aniline is replaced by 3-nitroaniline, to finally obtain compound D 08 as a yellow powder with a yield of 78%.
  • Embodiment 79
  • the preparation method is the same as that of Example 53, except that 6-bromo-1H-indole-3-carboxylic acid is replaced by 6-bromoindole-2-carboxylic acid, and aniline is replaced by 3-methylaniline, to finally obtain compound D 09 as a white needle-shaped solid with a yield of 39%.
  • Embodiment 80 is a diagrammatic representation of Embodiment 80.
  • the preparation method is the same as that of Example 53, except that 6-bromo-1H-indole-3-carboxylic acid is replaced by 6-bromoindole-2-carboxylic acid, and aniline is replaced by 2-bromoaniline, to finally obtain compound D 10 as a light yellow solid with a yield of 28%.
  • Embodiment 81
  • the preparation method is the same as that of Example 53, except that 6-bromo-1H-indole-3-carboxylic acid is replaced by 6-bromoindole-2-carboxylic acid, and aniline is replaced by 4-bromoaniline, to finally obtain compound D 11 as a white solid with a yield of 81%.
  • Embodiment 82
  • the preparation method was the same as that of Example 53, except that 6-bromo-1H-indole-3-carboxylic acid was replaced by 6-bromoindole-2-carboxylic acid, and aniline was replaced by 3,5-dibromoaniline, to finally obtain compound D 12 as a white solid with a yield of 31%.
  • Embodiment 83
  • the preparation method is the same as that of Example 53, except that 6-bromo-1H-indole-3-carboxylic acid is replaced by 6-bromoindole-2-carboxylic acid, and aniline is replaced by cyclohexylamine, to finally obtain compound D 13 as a light yellow solid with a yield of 90%.
  • Embodiment 84
  • the preparation method is the same as that of Example 53, except that 6-bromo-1H-indole-3-carboxylic acid is replaced by 6-bromoindole-2-carboxylic acid, and aniline is replaced by cyclopentylamine, to finally obtain compound D 14 as a milky white solid with a yield of 70%.
  • Embodiment 85 is a diagrammatic representation of Embodiment 85.
  • the preparation method is the same as that of Example 53, except that 6-bromo-1H-indole-3-carboxylic acid is replaced by 6-bromoindole-2-carboxylic acid, and aniline is replaced by 2-aminothiazole, to finally obtain compound D 15 as a light yellow solid with a yield of 13%.
  • Embodiment 86
  • the preparation method is the same as that of Example 53, except that 6-bromo-1H-indole-3-carboxylic acid is replaced by 6-bromoindole-2-carboxylic acid, and aniline is replaced by 2-aminopyridine, to finally obtain compound D 16 as a white solid with a yield of 9%.
  • Embodiment 87
  • the preparation method is the same as that of Example 53, except that 6-bromo-1H-indole-3-carboxylic acid is replaced by 6-bromoindole-2-carboxylic acid, and aniline is replaced by 3-aminopyridine, to finally obtain compound D 17 as a white solid with a yield of 75%.
  • Embodiment 88
  • the preparation method is the same as that of Example 53, except that 6-bromo-1H-indole-3-carboxylic acid is replaced by indole-2-carboxylic acid, and aniline is replaced by 3-bromoaniline, to finally obtain compound D 18 as a white block solid with a yield of 23%.
  • Embodiment 89
  • the preparation method is the same as that of Example 53, except that 6-bromo-1H-indole-3-carboxylic acid is replaced by 6-fluoroindole-2-carboxylic acid, and compound D19 is finally obtained as a light yellow solid with a yield of 79%.
  • Embodiment 90 is a diagrammatic representation of Embodiment 90.
  • the preparation method is the same as that of Example 53, except that 6-bromo-1H-indole-3-carboxylic acid is replaced by 5-methoxyindole-2-carboxylic acid, to finally obtain compound D 20 as a brown solid with a yield of 65%.
  • cAMP is a key signaling molecule for many G protein-coupled receptors.
  • the accumulation level of cAMP is mainly tested using GloSensor, a bioluminescence-based biosensor that can directly detect intracellular cAMP (Promega).
  • GloSensor a bioluminescence-based biosensor that can directly detect intracellular cAMP (Promega).
  • the principle is to insert a cAMP binding domain into the N-terminus and C-terminus of firefly luciferase through genetic engineering technology to make the enzyme in an inactive state.
  • the enzyme is activated, thereby oxidizing the substrate luciferin to produce bioluminescence.
  • the cAMP accumulation experiment is used to test the functional activity of the target compound on ⁇ 2AR and to clarify whether the new compound is a negative allosteric modulator (NAM) of ⁇ 2AR .
  • NAM negative allosteric modulator
  • HEK 293T cells were seeded in 6-well plates, with 4 ⁇ 10 5 cells per well.
  • ⁇ 2AR and pGloSensor-22F cAMP plasmids were transfected into HEK 293T cells simultaneously using FuGene transfection reagent (Promega).
  • the transfected cells were washed with CO2- independent medium and incubated with a 2% v/v GloSensor cAMP reagent stock solution (dissolved in CO2- independent medium containing 10% FBS). After incubation at 37°C for 1 hour and then at room temperature for 1 hour, the bioluminescent signal was detected by a multifunctional microplate reader until a steady-state baseline signal was obtained. Then, different concentration gradients of the new derivative and the control compound Cmpd-15 were added to the cells, and the positive control ISO (final concentration 1nM-100 ⁇ M) was added after incubation at 37°C for 30 minutes. The changes in bioluminescence were read with a microplate reader.
  • the GloSensor cAMP accumulation test was used to compare the allosteric antagonistic activity of the new pyrazole derivatives (final concentration of 50 ⁇ M) with the lead compound Cmpd-15, using different concentration gradients of isoproterenol (ISO) as the positive control (final concentration of 1nM-100 ⁇ M) and compound Cmpd-15 (final concentration of 50 ⁇ M) as the reference control.
  • ISO isoproterenol
  • Table 2 show that most compounds have allosteric antagonistic activity against ⁇ 2AR, among which compound B8 has the highest activity, which is 4.17 times that of Cmpd-15.
  • the cAMP accumulation test was used to further study the allosteric antagonism mechanism, and the target compounds were tested to determine whether they could allosterically regulate the functional activity of the ⁇ 2 -AR endogenous ligand ISO to determine whether they were ⁇ 2 -AR negative allosteric modulators (NAMs).
  • NAMs negative allosteric modulators
  • the new compounds (1nM-100 ⁇ M) with multiple concentrations were first added to the cells, and after incubation at 37°C for 30 minutes, different concentration gradients of positive control ISO (final concentration 1nM-100 ⁇ M) were added to the cells to test whether the change in bioluminescence at this time showed a concentration-dependent limited downward trend.
  • the specific experimental steps were the same as the above Glosensor cAMP accumulation test.
  • the experimental results showed that the target compounds A08, A26, B8, C01, C15, and C17 could negatively allosterically regulate the functional activity of the ⁇ 2 -AR endogenous ligand ISO.

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Abstract

La présente invention appartient au domaine de la chimie pharmaceutique, et divulgue en particulier l'utilisation d'un composé benzoazacyclique en tant que modulateur allostérique d'un β2-adrénorécepteur. Le composé benzoazacyclique de la présente invention a une structure telle que représentée dans la formule (I), dans laquelle X représente N ou CH ; Y représente N ou CH ; R1 représente l'un quelconque ou plusieurs parmi H, un groupe méthyle, méthoxy, phényle, F, Cl, Br, I, CN, NO2, NH2, OH et CF3 en une position quelconque sur un cycle benzène ; R2 représente l'un quelconque parmi H, un groupe méthyle, phényle et benzyle ; R3 représente l'un quelconque parmi un atome d'hydrogène et un groupe alkyle ; et R4 représente l'un quelconque parmi H, un groupe alkyle, cycloalkyle, phényle, phényle substitué et benzyle substitué. Les résultats pharmacologiques montrent que la plupart des composés benzoazacycliques synthétisés présentent une bonne activité antagoniste allostérique sur β2-AR, et peuvent moduler négativement l'activité fonctionnelle du récepteur.
PCT/CN2023/132226 2023-07-28 2023-11-17 UTILISATION D'UN COMPOSÉ BENZOAZACYCLIQUE EN TANT QUE MODULATEUR ALLOSTÉRIQUE D'UN β2-ADRÉNORÉCEPTEUR WO2024109642A1 (fr)

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CN202310937574.0A CN116874432A (zh) 2023-07-28 2023-07-28 用作β2-肾上腺素受体别构拮抗剂的苯并咪唑类衍生物
CN202311189427.6 2023-09-14
CN202311189427.6A CN117229217A (zh) 2023-09-14 2023-09-14 一种肾上腺素受体功能活性的别构调节剂及其制备方法和应用
CN202311215367.0 2023-09-20
CN202311215367.0A CN117447381A (zh) 2023-09-20 2023-09-20 吲哚酰胺类衍生物及其在制备β2肾上腺素受体别构拮抗剂药物中的应用

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