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Benzo [c] [1, 2] oxaborolane-1 (3H)-alcohol compound and application thereof

A compound and hydrate technology, applied in the field of biomedicine, can solve problems such as central nervous system disorders, and achieve high activity, good regulatory activity, and good economic value.

Pending Publication Date: 2022-03-08
HUBEI UNIV FOR NATITIES
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, questions about efficacy and adverse side effects, such as vomiting and central nervous system disturbances, remain unresolved

Method used

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  • Benzo [c] [1, 2] oxaborolane-1 (3H)-alcohol compound and application thereof
  • Benzo [c] [1, 2] oxaborolane-1 (3H)-alcohol compound and application thereof
  • Benzo [c] [1, 2] oxaborolane-1 (3H)-alcohol compound and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0048] 2-((1-Hydroxy-1,3-dihydrobenzo[c][1,2]oxaborin-6-yl)methyl)-1-oxo-1,2,3,4 -Tetrahydroisoquinoline-6-carbonitrile

[0049]

[0050] first step:

[0051] Compound 1a (31.4g, 200.0mmol) and methanesulfonic acid (50ml) were dissolved in dichloromethane (200ml), and NaN was added under ice-cooling 3 (26g, 400.0mmol), stirred and reacted at room temperature for 12 hours, TLC detected the reaction, after the reaction was completed, the reaction solution was poured into 10% aqueous sodium hydroxide solution (500ml), extracted with dichloromethane (200ml×2), the combined organic layers were dried, Column chromatography separated to obtain 25.7 g of off-white solid with a yield of 74.7%.

[0052] Step two:

[0053] Compound 1b (25.0g, 145.3mmol) was dissolved in DMF (200ml), sodium hydride (4.2g, 174.4mmol) was added at room temperature, stirred for 1 hour, then compound 1c (44.4g, 145.3mmol) was added, at 40°C The reaction was stirred for 4 hours, and the reaction was det...

Embodiment 2

[0059] 2-((1-Hydroxy-1,3-dihydrobenzo[c][1,2]oxaborin-6-yl)methyl)-1-oxo-1,2,3,4 -Tetrahydroisoquinoline-5-carbonitrile

[0060]

[0061] first step:

[0062] Compound 2a (15.7g, 100.0mmol) and methanesulfonic acid (30ml) were dissolved in dichloromethane (200ml), and NaN3 (13g, 200.0mmol) was added under ice-cooling, stirred at room temperature for 12 hours, and TLC detected the reaction. After the reaction was completed, the reaction solution was poured into 10% aqueous sodium hydroxide solution (500ml), extracted with dichloromethane (200ml×2), the organic layers were combined, dried, and separated by column chromatography to obtain 12.1g of an off-white solid with a yield of 70.3%.

[0063] Step two:

[0064] Compound 2b (12.0g, 69.8mmol) was dissolved in DMF (100ml), sodium hydride (3.3g, 137.5mmol) was added at room temperature, stirred for 1 hour, then compound 1c (21.4g, 69.8mmol) was added, at 40°C The reaction was stirred for 4 hours, and the reaction was detec...

Embodiment 3

[0070] 2-((1-Hydroxy-1,3-dihydrobenzo[c][1,2]oxaborin-6-yl)methyl)-1-oxo-1,2,3,4 -Tetrahydroisoquinoline-7-carbonitrile

[0071]

[0072] first step:

[0073] Compound 3a (15.7g, 100.0mmol) and methanesulfonic acid (30ml) were dissolved in dichloromethane (200ml), and NaN was added under ice-cooling 3 (13.0g, 200.0mmol), stirred and reacted at room temperature for 12 hours, TLC detected the reaction, after the reaction was completed, the reaction solution was poured into 10% aqueous sodium hydroxide solution (500ml), extracted with dichloromethane (200ml×2), the organic layers were combined, and dried , and separated by column chromatography to obtain 12.7 g of off-white solid with a yield of 73.8%.

[0074] The second step to the fourth step refer to Example 1 to obtain the title compound (off-white solid 1.5 g, yield 47.2%), ESI (+) m / z = 319.1.

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PUM

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Abstract

The invention discloses a benzo [c] [1, 2] oxaborolane-1 (3H)-alcohol compound and application thereof, and further relates to a pharmaceutical composition containing the benzo [c] [1, 2] oxaborolane-1 (3H)-alcohol compound and application of the pharmaceutical composition. The benzo [c] [1, 2] oxaborolane-1 (3H)-alcohol compound or the pharmaceutical composition can be used for inhibiting PDE4 (Phosphate Dehydrogenase 4). The invention provides a compound as shown in a formula I, and a stereoisomer, a solvate, a hydrate or a pharmaceutically acceptable salt thereof. The compound I provided by the invention has the advantages of high pharmacodynamic activity and simple synthesis steps, and has good clinical value and economic value.

Description

Technical field: [0001] The invention belongs to the technical field of biomedicine, and specifically relates to benzo[c][1,2]oxaborolane-1(3H)-alcohol derivatives with PDE4 inhibitory effect, preparation method, composition and application. Background technique [0002] Cyclic AMP (cAMP) is a second messenger that mediates the biological response of cells to a wide range of extracellular stimuli. When an appropriate agonist binds to a specific cell surface receptor, adenylyl cyclase is activated to convert adenosine triphosphate (ATP) into cAMP. Studies have shown that the intracellular action of agonist-induced cAMP is mainly mediated by the action of cAMP-dependent protein kinase, which is terminated by nucleotide transport to the extracellular space or by enzymatic cleavage by nucleoside phosphodiesterase (PDE) Intracellular action of cAMP, hydrolyzed by phosphodiesterase to the inactive metabolite 5'-adenosine phosphate (5'-AMP). In cells of human myeloid and lymphoid...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07F5/02A61K31/69A61P29/00A61P19/02A61P43/00A61P11/00A61P11/06A61P17/00
CPCC07F5/02A61P29/00A61P19/02A61P43/00A61P11/00A61P11/06A61P17/00
Inventor 田从魁刘宣呈朱姝安吴增宝娄方明焦龙华
Owner HUBEI UNIV FOR NATITIES