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Adrenergic receptor modulating compounds and methods of using same

A technology of adrenaline and compounds, applied in the field of adrenergic receptor modulating compounds and their use

Inactive Publication Date: 2019-02-05
THE BOARD OF TRUSTEES OF THE LELAND STANFORD JUNIOR UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the discovery of subtype-selective ligands has been challenging due to the high levels of sequence homology shared by these subtypes

Method used

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  • Adrenergic receptor modulating compounds and methods of using same
  • Adrenergic receptor modulating compounds and methods of using same
  • Adrenergic receptor modulating compounds and methods of using same

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0400] Example 1: Exemplary synthesis of compounds The following representative synthetic methods and strategies can be applied to prepare the subject compounds.

[0401] plan 1:

[0402]

[0403] Reagents and conditions: a, hydrazine hydrate, ethylene glycol, 25-160℃, 2.5 hours; B, (R)-epichlorohydrin, CSF, DMF, 50℃, 48 hours; C, 4,2-propanol , 50°C, 12 hours.

[0404] 3-Methyl-1H-indazol-4-ol (2): The 1-(2,6-dihydroxyphenyl)ethan-1-one (1) (5.0g, 32.86mmol) in ethylene glycol ( 70ml) was added to a solution of hydrazine hydrate (3.29g, 65.72mmol) in ethylene glycol (20mL). The reaction mixture was stirred at room temperature for 20 minutes and then heated at 160°C for an additional 2 hours. After cooling to room temperature and diluting with water (200 mL), HOAc (2.5 ml) was added to adjust pH=6. The resulting mixture was extracted with EtOAc (3×50 ml). The organic layer was washed with brine and subjected to Na 2 SO 4 Dry, filter, and concentrate the filtrate under reduced ...

Embodiment 2

[0451] Example 2: Synthesis of compound

[0452] Reaction scheme: Step 1

[0453] Process: To a mixture of 1-(2,6-dihydroxyphenyl)ethanone (10g, 65.7mmol) in ethylene glycol (140mL) was added hydrazine hydrate (6.58g, 131.4mmol) in ethylene glycol (40mL ) Solution. The reaction mixture was stirred at room temperature for 20 minutes and at 160°C for an additional 2 hours. After cooling to ambient temperature, the RM was diluted with water (400 mL). Acetic acid (5 mL) was added to adjust pH=6. The resulting mixture was extracted with EtOAc (3×100 mL). The organic layer was washed with brine and subjected to Na 2 SO 4 It was dried, filtered, concentrated under reduced pressure, and purified by crystallization (9.9 g, 100%) as a brown solid.

[0454] Reaction scheme: Step 2

[0455]

[0456] Process: To the product of step-1 (2g, 13.5mmol), TEA (5.61mL, 40.4mmol) and DMAP (100mg) in anhydrous THF (35mL) was added dropwise (BOC) at -15°C 2 A solution of O (2.94 g, 13.5 mmol) in THF (...

Embodiment 3

[0545] Example 3: Assay for evaluating compounds

[0546] Assays that may be suitable for assessing the activity of the subject compound include those described by Shamloo et al., Neurobiology of Disease 43 (2011) 397-413. In addition, the following materials and general methods can be adapted to assess the activity of the subject compound, for example, the modulation and pathology and activity of neuroinflammation in Alzheimer's disease (AD) models.

[0547] Behavior test

[0548] Open field: Under low light conditions, evaluate general sports activities in a square field (76cm×76cm×50cm). The mouse was placed in a corner of the open field and allowed to explore freely for 10 minutes while being tracked from a camera installed on the ceiling by an automatic tracking system (Ethovision). At the end of each test, the surface of the field was cleaned with 1% Virkon disinfectant.

[0549] Activity Room : Evaluate general motor activity as previously described (Shamloo et al., (2011)...

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Abstract

Adrenergic receptor modulating compounds and methods of using the same are provided. Also provided are methods of treating a subject for a disease or condition associated with an adrenergic receptor including administering a therapeutically effective amount of the subject compound. Aspects of the disclosure include a method of modulating an inflammatory pathway in a cell, such as the production ofTNF-[alpha] in the cell. The method can include contacting a cell with a [beta]1-selective adrenergic receptor modulating compound to selectively activate a cAMP pathway over a [beta]-arrestin pathway in the cell. Pharmaceutical compositions and kits which include the subject compounds are provided.

Description

[0001] cross reference [0002] This application claims the benefit of U.S. Provisional Patent Application 62 / 336,370 filed on May 13, 2016, which is incorporated herein by reference in its entirety. [0003] Government Support Statement [0004] The present invention was completed with government support under contract TR001085 awarded by the National Institutes of Health. The government has certain rights in this invention. Background technique [0005] Adrenergic receptors (ADR) are G protein-coupled receptors (GPCR), which are widely expressed throughout the body and play an important role in regulating a variety of physiological processes, including cognition, stress-related behaviors, inflammation and smooth muscle contraction / dilation, Heart muscle contraction, airway response and cognition. In addition, adrenergic receptors are involved in many diseases. There are multiple subtypes. Because these subtypes are expressed in different patterns and participate in different phy...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/133A61K31/138A61K31/404C07D209/00C07D209/02C07D209/04
CPCA61K31/138A61K31/404A61K45/06A61K31/397A61K31/40A61K31/416A61K31/4164A61K31/421A61K31/445A61K31/495A61K31/5375C07D231/56C07D401/12C07D405/12C07D205/04C07D295/185C07D403/12A61P25/28A61P43/00A61K2300/00A61P9/10A61P35/00A61P11/00A61P29/00A61K31/216A61K31/4453A61K31/5377
Inventor M·沙姆洛A·贾汉吉尔B·易A·K·埃文斯M·J·格林
Owner THE BOARD OF TRUSTEES OF THE LELAND STANFORD JUNIOR UNIV
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