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WO2023165168A1 - APPLICATION D'UN DÉRIVÉ DE PYRAZOLE EN TANT QUE MODULATEUR, ANTAGONISTE ET AGONISTE ALLOSTÉRIQUE DU RÉCEPTEUR ADRÉNERGIQUE β2 - Google Patents

APPLICATION D'UN DÉRIVÉ DE PYRAZOLE EN TANT QUE MODULATEUR, ANTAGONISTE ET AGONISTE ALLOSTÉRIQUE DU RÉCEPTEUR ADRÉNERGIQUE β2 Download PDF

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Publication number
WO2023165168A1
WO2023165168A1 PCT/CN2022/132704 CN2022132704W WO2023165168A1 WO 2023165168 A1 WO2023165168 A1 WO 2023165168A1 CN 2022132704 W CN2022132704 W CN 2022132704W WO 2023165168 A1 WO2023165168 A1 WO 2023165168A1
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Prior art keywords
nmr
dmso
pyrazole
bromophenyl
preparation
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Ceased
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PCT/CN2022/132704
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English (en)
Chinese (zh)
Inventor
陈新
黑晓源
雒智杰
戚颖
钱明成
赵帅
李晴
洪美龄
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Changzhou University
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Changzhou University
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Priority claimed from CN202211323580.9A external-priority patent/CN115894373B/zh
Priority claimed from CN202211403416.9A external-priority patent/CN115745891B/zh
Application filed by Changzhou University filed Critical Changzhou University
Publication of WO2023165168A1 publication Critical patent/WO2023165168A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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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
    • A61K31/41—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
    • A61K31/415—1,2-Diazoles
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members 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 to ring carbon atoms

Definitions

  • the invention belongs to the field of medicinal chemistry, and in particular relates to a preparation method of pyrazole derivatives and their application as allosteric regulators of ⁇ 2 adrenergic receptors.
  • GPCR G-protein coupled receptor
  • rhodopsin rhodopsin
  • Adrenergic receptors (AR) are a type A subfamily of GPCRs that play an important role in the sympathetic nervous system. For example, ⁇ 1 -adrenoceptor ( ⁇ 1 AR) antagonists are used in cardiovascular disease, while ⁇ 2 -adrenergic receptor ( ⁇ 2 AR) antagonists are used in the treatment of asthma.
  • Allosteric ligands (also known as allosteric ligands) affect receptor activity by differing in conformation from the orthosteric ligand binding site. Allosteric ligands mediate the action of GPCR proteins by inducing conformational changes in their proteins, which shift from the allosteric binding pocket to the orthosteric site or directly to the effector protein coupling site. Due to the relatively low conservation of their binding sites, it is possible with better subtype selectivity. Drugs targeting allosteric classes in GPCRs not only have better selectivity than traditional drugs, but also reduce potential drug side effects caused by off-target effects.
  • allosteric modulators can also act synergistically with orthosteric ligands to lock the receptor in a specific conformation, so that the receptor exhibits specific signal transduction, which in turn makes the allosteric modulator different from the orthosteric ligand.
  • Pharmacodynamic properties of ligands. ⁇ 2 AR antagonists are very classic GPCRs drugs, which play an important role in the treatment of heart failure, hypertension, coronary heart disease, arrhythmia, angina pectoris and other diseases, and are the cornerstone of the treatment of cardiovascular diseases. Therefore, the development and design of ⁇ 2 AR allosteric antagonists is of great significance to the treatment of various cardiovascular diseases.
  • Cmpd-15 small molecule negative allosteric modulator compound 15
  • Cmpd-15 shown in formula 2
  • Cmpd-15 is a peptide compound with poor water solubility and low biological activity, the relative instability of its structure may affect its druggability.
  • Pyrazole (C 3 H 3 N 2 H) is a nitrogen-containing heterocyclic compound with good stability and broad-spectrum pharmacological properties, and has become an attractive core skeleton in drug design.
  • the present invention uses a scaffold-hopping strategy to replace the peptide core structure of Cmpd-15 with a pyrazole skeleton. Based on the skeleton transition strategy, the key functional groups of the three parts of Cmpd-15 were retained to form heterocyclic derivatives with pyrazole as the core structure, and the activity and specificity of the new heterocyclic derivatives on ⁇ 2 AR were evaluated.
  • the design idea of the new heterocyclic derivatives is shown in Formula 3.
  • the pharmacophore on the left, middle and right side of Cmpd-15 is respectively connected to the pyrazole ring to form a pyrazole type compound. It is estimated that the stability of the designed heterocyclic derivatives is better than that of Cmpd-15, and it is possible to improve the ability to combine with ⁇ 2 AR, and the druggability is also relatively good.
  • the invention uses acetophenones with different substituents as raw materials, undergoes Claisen condensation, ring formation, substitution, ester hydrolysis and amide coupling reactions to finally obtain a series of new pyrazole derivatives.
  • the purpose of the present invention is to develop a new heterocyclic derivative with stable chemical structure, high biological activity, good receptor subtype selectivity and improved water solubility, as an allosteric regulator of ⁇ 2 -AR, for the development of cardiovascular and cerebrovascular, New medicines for diabetes and cancer diseases offer new directions.
  • the solvent is N,N-dimethylformamide; the activator is 1-hydroxy-7-azabenzotriazole (HOAT); the acid-binding agent is N-methylmorpholine (NMM); the amide coupling Agent 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride (EDCI); Compound 5: HOAT: Compound A: NMM: The molar ratio of EDCI is 1:1.2:1:0.7: 1.2; react in ice bath for 1.5h, and react at room temperature for 12h.
  • New pyrazole derivatives can be used as agonists, antagonists, allosteric agonists and allosteric antagonists of ⁇ 2 -AR;
  • compounds H 30 , H 31 , and H 32 in Table 1-1 have agonist activity and can be used as ⁇ 2 -AR agonists;
  • the compound H 31 in Table 1-1 has both agonistic activity and allosteric activity, and can be used as an allosteric agonist of ⁇ 2 -AR;
  • H 2 , H 22 , H 23 , H 34 , H 54 , H 55 , I 2 , I 4 , I 6 and compounds L 1 -L 22 in Table 1-1 and Table 1-2 have both antagonistic activity and Allosteric activity, can be used as an allosteric antagonist of ⁇ 2 -AR.
  • New pyrazole derivatives can be used as agonists, antagonists, allosteric agonists and allosteric antagonists of ⁇ 2 -AR, providing new directions for the development of new drugs for cardiovascular and cerebrovascular diseases, diabetes and cancer diseases.
  • Fig. 1 is the structural diagram and ISO dose-response curve of H31 ;
  • Figure 2 is the EC 50 curves of compounds H 30 , H 31 , and H 32 .
  • Figure 3 is a dose-response curve of ISO mediated by L1, L4, and L14.
  • Figure 4 is a graph partially representative of pyrazole compound-mediated antagonism.
  • Step 1 Preparation of ethyl 2,4-dioxo-4-phenylbutyrate
  • Step 4 Preparation of N-2 benzyl-phenylpyrazole-1-carboxylic acid
  • N-2 benzyl-phenylpyrazole-1-carboxylic acid (30mg, 0.1mmol) and HOAT (24.5mg, 0.2mmol) were dissolved in 5mL DMF, stirred at room temperature for 10min under nitrogen protection, and compound ( S)-2-amino-3-(3-bromophenyl)-N-methylpropionamide (38.5mg, 0.1mmol), after stirring for 10min, N-methylmorpholine (0.009mL, 008mmol), stirred for 10min, added EDCI (24.8mg, 0.1mmol), kept stirring at 0°C for 1h, and reacted at room temperature for 12h.
  • Embodiment 6 is a diagrammatic representation of Embodiment 6
  • 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:
  • Example 2 change benzyl chloride into 3-bromobenzyl chloride, change compound (S)-2-amino-3-(3-bromophenyl)-N-methylpropionamide into compound ( S)-2-amino-3-(3,5-dichlorophenyl)-N-methylpropanamide, the product is a white solid, and the yield is 73%.
  • Example 2 change benzyl chloride into 3-bromobenzyl chloride, change compound (S)-2-amino-3-(3-bromophenyl)-N-methylpropionamide into compound ( S)-2-amino-3-(3,5-difluorophenyl)-N-methylpropanamide, the product is a white solid, and the yield is 72%.
  • Example 2 change benzyl chloride into 3-bromobenzyl chloride, change compound (S)-2-amino-3-(3-bromophenyl)-N-methylpropionamide into compound ( S)-2-amino-3-(3-bromo-5-fluorophenyl)-N-methylpropanamide, the product is a white solid with a yield of 74%.
  • Example 2 change benzyl chloride into 3-bromobenzyl chloride, change compound (S)-2-amino-3-(3-bromophenyl)-N-methylpropionamide into compound ( S)-2-amino-3-(2-bromophenyl)-N-methylpropanamide, the product is a white solid, and the yield is 66%.
  • Example 2 change benzyl chloride into 3-bromobenzyl chloride, change compound (S)-2-amino-3-(3-bromophenyl)-N-methylpropionamide into compound ( S)-2-amino-3-(4-bromophenyl)-N-methylpropanamide, the product is a white solid, and the yield is 70%.
  • Example 2 change benzyl chloride into 3-bromobenzyl chloride, change compound (S)-2-amino-3-(3-bromophenyl)-N-methylpropionamide into compound 2 -Amino-3-(3-bromophenyl)-N-methylpropanamide, the product is a white solid with a yield of 73%.
  • Step 1 Preparation of ethyl 4-(2-bromophenyl)-2,4-dioxobutanoate
  • Step 3 Preparation of ethyl 1-benzyl-5-(2-bromophenyl)-1H-pyrazole-3-carboxylate
  • Step 5 (S)-1-Benzyl-5-(2-bromophenyl)-N-(3-(3-bromophenyl)-1-(methylamino)-1-oxopropane-2 Preparation of -yl)-1H-pyrazole-3-carboxamide
  • Example 57 Other conditions were the same as in Example 57, except that 2-bromoacetophenone was changed to acetophenone, benzyl chloride was changed to 3-fluorobenzyl chloride, and the product was a white solid with a yield of 73%.
  • Step 1 Preparation of ethyl 4-(2-fluorophenyl)-2,4-dioxobutanoate
  • Step 4 (S)-N-(3-(3-bromophenyl)-1-(methylamino)-1-oxopropan-2-yl)-3-(2-fluorophenyl)-1H- Preparation of pyrazole-5-carboxamide
  • Example 66 Other conditions were the same as in Example 66, and 4-fluoroacetophenone was substituted for 2-fluoroacetophenone to obtain a white solid with a yield of 35%.
  • Example 66 Other conditions were the same as in Example 66, and 4-chloroacetophenone was substituted for 2-fluoroacetophenone to obtain a white solid with a yield of 35%.
  • Example 66 Other conditions were the same as in Example 66, and 3-methylacetophenone was substituted for 2-fluoroacetophenone to obtain a white solid with a yield of 35%.
  • Example 66 Other conditions are the same as in Example 66, replacing 2-fluoroacetophenone with acetophenone, and replacing (S)-2-amino-3-(3-bromophenyl)-N-methylpropionamide with (S)- 2-Amino-3-(3,5-difluorophenyl)-N-methylpropanamide, a white solid was obtained with a yield of 37%.
  • Example 66 Other conditions are the same as in Example 66, replacing 2-fluoroacetophenone with acetophenone, and replacing (S)-2-amino-3-(3-bromophenyl)-N-methylpropionamide with (S)- 2-Amino-3-(3,5-dichlorophenyl)-N-methylpropanamide, a white solid was obtained with a yield of 38%.
  • Example 66 Other conditions are the same as in Example 66, replacing 2-fluoroacetophenone with acetophenone, and replacing (S)-2-amino-3-(3-bromophenyl)-N-methylpropionamide with (S)- 2-Amino-3-(3,5-dibromophenyl)-N-methylpropanamide was obtained as a white solid with a yield of 39%.
  • Example 66 Other conditions are the same as in Example 66, replacing 2-fluoroacetophenone with acetophenone, and replacing (S)-2-amino-3-(3-bromophenyl)-N-methylpropionamide with (S)- 2-Amino-3-(3-bromo-5-fluorophenyl)-N-methylpropanamide, a white solid was obtained with a yield of 35%.
  • Example 66 Other conditions are the same as in Example 66, replacing 2-fluoroacetophenone with acetophenone, and replacing (S)-2-amino-3-(3-bromophenyl)-N-methylpropionamide with (S)- 2-Amino-3-(2-bromophenyl)-N-methylpropanamide, a white solid was obtained with a yield of 37%.
  • Example 66 Other conditions are the same as in Example 66, replacing 2-fluoroacetophenone with acetophenone, and replacing (S)-2-amino-3-(3-bromophenyl)-N-methylpropionamide with (S)- 2-Amino-3-(4-bromophenyl)-N-methylpropanamide, a white solid was obtained with a yield of 35%.
  • cAMP a bioluminescence based cAMP biosensor (Promega).
  • HEK293T cells in good condition were planted in 6-well plates or 35MM cell culture dishes, and placed in a 37°C, 5% CO 2 incubator for 24 hours to allow the cells to adhere to the wall and grow.
  • the ⁇ 2 adrenoreceptor plasmid and the pGloSensor TM -22FcAMP plasmid were transferred into the cells with a transfection reagent, and placed in a 5% CO 2 incubator at 37°C for 24 hours to allow the transcription and expression of the target gene.
  • the cells transfected with the plasmid were evenly seeded in a 96-well plate, and cultured at 37° C. in a 5% CO 2 incubator for 24 hours. Finally, discard the old culture medium in the 96-well plate, wash the cells with new culture medium, and then add the balanced culture medium containing GloSensor TM cAMP Reagent, serum and CO 2 -independent medium at 37°C, 5% CO 2 incubator Incubate for 1-2 hours or until a stable background signal is obtained.
  • Isoproterenol (ISO) was dissolved in DMSO, and after sterile filtration, it was used as the compound mother solution and diluted with culture medium to different concentration gradients (the DMSO concentration in the prepared compound was less than or equal to 0.1%).
  • the prepared compound was quickly added to the 96-well plate containing HEK293T cells to start administration stimulation.
  • the bioluminescent signal after adding the compound can be observed by a multi-functional microplate reader. When the signal value rises to the peak and no longer increases, immediately add the compound with different concentration gradients (8 ⁇ M, 20 ⁇ M, 50 ⁇ M, 100 ⁇ M).
  • the bioluminescent signal was collected immediately with a multifunctional microplate reader, and the value of the bioluminescent signal increased with the increase of the compound concentration.
  • the data was sorted and processed with GraphPad Prism8 software, with the concentration as the abscissa, and the signal value, multiple value response value as the ordinate, to obtain the dose-effect relationship curve of the agonist, antagonist and allosteric modulator and the EC 50 or IC 50 of the compound value.
  • compound H 31 not only has the effect of agonizing ⁇ 2 AR, but also can positively regulate the functional activity of ⁇ 2 AR agonist ISO .
  • the dose-effect curve of ISO showed a limited upward trend ( Figure 1).
  • Compounds L 1 , L 4 , and L 14 can negatively regulate the functional activity of ⁇ 2 AR endogenous ligand ISO, and are allosteric antagonists of ⁇ 2 -adrenergic receptors.
  • the dose-effect curve of ISO showed a limited downward trend ( Figure 3).

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Abstract

La présente invention concerne une application d'un dérivé de pyrazole en tant que modulateur, antagoniste et agoniste allostérique du récepteur adrénergique β 2. Une acétophénone ou une acétophénone contenant différents substituants est utilisée en tant que matière première initiale, et finalement le dérivé de pyrazole tel que représenté dans la formule (1) est obtenu.
PCT/CN2022/132704 2022-10-27 2022-11-18 APPLICATION D'UN DÉRIVÉ DE PYRAZOLE EN TANT QUE MODULATEUR, ANTAGONISTE ET AGONISTE ALLOSTÉRIQUE DU RÉCEPTEUR ADRÉNERGIQUE β2 Ceased WO2023165168A1 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
CN202211323580.9A CN115894373B (zh) 2022-10-27 2022-10-27 N-取代苄基吡唑衍生物在作为β2肾上腺素受体调节剂、拮抗剂和激动剂的应用
CN202211323580.9 2022-10-27
CN202211403416.9A CN115745891B (zh) 2022-11-10 2022-11-10 吡唑衍生物在作为β2-肾上腺素受体拮抗剂的应用
CN202211403416.9 2022-11-10

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN115745891A (zh) * 2022-11-10 2023-03-07 常州大学 吡唑衍生物在作为β2-肾上腺素受体别构拮抗剂的应用
CN115894373A (zh) * 2022-10-27 2023-04-04 常州大学 N-取代苄基吡唑衍生物在作为β2肾上腺素受体别构调节剂、拮抗剂和激动剂的应用

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004104001A2 (fr) * 2003-05-21 2004-12-02 Prosidion Limited Inhibiteurs d'amide d'acide pyrrolopyridine-2-carboxylique de la glycogene phosphorylase
CN106749511A (zh) * 2017-01-09 2017-05-31 常州大学 苯丙氨酸二肽苯乙酰胺衍生物及其制备方法和用途
CN114057646A (zh) * 2021-12-14 2022-02-18 常州大学 一种吡唑衍生物及其在制备抗肿瘤药物方面的应用

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004104001A2 (fr) * 2003-05-21 2004-12-02 Prosidion Limited Inhibiteurs d'amide d'acide pyrrolopyridine-2-carboxylique de la glycogene phosphorylase
CN106749511A (zh) * 2017-01-09 2017-05-31 常州大学 苯丙氨酸二肽苯乙酰胺衍生物及其制备方法和用途
CN114057646A (zh) * 2021-12-14 2022-02-18 常州大学 一种吡唑衍生物及其在制备抗肿瘤药物方面的应用

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN115894373A (zh) * 2022-10-27 2023-04-04 常州大学 N-取代苄基吡唑衍生物在作为β2肾上腺素受体别构调节剂、拮抗剂和激动剂的应用
CN115894373B (zh) * 2022-10-27 2025-08-01 常州大学 N-取代苄基吡唑衍生物在作为β2肾上腺素受体调节剂、拮抗剂和激动剂的应用
CN115745891A (zh) * 2022-11-10 2023-03-07 常州大学 吡唑衍生物在作为β2-肾上腺素受体别构拮抗剂的应用
CN115745891B (zh) * 2022-11-10 2025-08-01 常州大学 吡唑衍生物在作为β2-肾上腺素受体拮抗剂的应用

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