Tetrazolone substituted steroids and use thereof

An unsubstituted, compound technology for use in the field of tetrazolinone-substituted steroids and their uses to solve the problem of not always being effective in treating a desired syndrome

Active Publication Date: 2021-08-24
BEIJING XUANYI PHARMASCIENCES CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0008] Many NAS therapeutic compounds suffer from toxicity, formulation issues and are not always effective in treating desired syndromes

Method used

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  • Tetrazolone substituted steroids and use thereof
  • Tetrazolone substituted steroids and use thereof
  • Tetrazolone substituted steroids and use thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0489] Example 1: 2-bromo-1-((3R,5R,8R,9R,10S,13S,14S,17S)-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopentadiene Synthesis of [a]phenanthrene-17-yl)ethan-1-one (compound 7)

[0490] Compound 7 was synthesized according to the procedure disclosed in patent PCT / CN2014 / 075594 and J.Med.Chem.2017,60,7810-7819.

[0491] Step 1: (5R,8R,9R,10S,13S,14S)-13-Methyltetrahydro-3H-cyclopenta[a]phenanthrene-3,17(2H)-dione (compound 2) Synthesis

[0492]

[0493] A mixture of compound 1 (50.0 g, 184.56 mmol, 1.0 eq), palladium black (2.5 g, 5% w / w) in tetrahydrofuran (300 mL) and concentrated hydrobromic acid (1 mL) was hydrogenated with hydrogen at 70 psi. The mixture was stirred at room temperature for 24 hours. The progress of the reaction mixture was monitored by TLC. After the reaction was complete, the mixture was filtered through a pad of celite and a sintered funnel, and the filtrate was concentrated under reduced pressure. The residue was recrystallized from acetone to obt...

Embodiment 2

[0509] Example 2: 1-(2-((3R,5R,8R,9R,10S,13S,14S,17S)-3-hydroxyl-3,13-dimethylhexadecahydro-1H-cyclopentadiene [a] Synthesis of phenanthrene-17-yl)-2-oxoethyl)-4-methyl-1,4-dihydro-5H-tetrazol-5-one (compound 8)

[0510]

[0511] To a suspension of potassium carbonate (42 mg, 0.303 mmol, 0.8 eq) in tetrahydrofuran (5 mL) was added 1-methyl-1,4-dihydro-5H-tetrazol-5-one (114 mg, 1.14 mmol, 3.0 eq ) and compound 7 (150 mg, 0.379 mmol, 1.0 eq). The mixture was stirred at room temperature for 15 hours. The progress of the reaction mixture was monitored by TLC (petroleum ether / ethyl acetate=3:1). After the reaction was complete, the mixture was poured into 10 mL of water and extracted with ethyl acetate (2×20 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residual mixture was purified by preparative HPLC to provide compound 8 (50 mg, 31%) as a white solid. TLC: PE / EA...

Embodiment 3

[0512] Example 3: 1-ethyl-4-(2-((3R,5R,8R,9R,10S,13S,14S,17S)-3-hydroxy-3,13-dimethylhexadecahydro-1H- Synthesis of Cyclopenta[a]phenanthrene-17-yl)-2-oxoethyl)-1,4-dihydro-5H-tetrazol-5-one (compound 11)

[0513] Step 1: Synthesis of 1-ethyl-1,4-dihydro-5H-tetrazol-5-one (compound 10)

[0514]

[0515] A stirred mixture of isocyanatoethane (1.0 g, 14.08 mmol, 1.0 eq) and azidotrimethylsilane (3.5 ml, 26.76 mmol, 1.9 eq) was heated to 100 °C and stirred for 16 h. The progress of the reaction mixture was monitored by TLC. After the reaction was complete, the mixture was cooled to room temperature and concentrated. The residue was diluted with ethyl acetate (10 mL) and extracted with saturated aqueous sodium bicarbonate (3 x 10 mL). With effective stirring, 6M hydrochloric acid was added to the combined aqueous layers to adjust pH<3, and extracted with ethyl acetate (3×20 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under redu...

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PUM

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Abstract

The present disclosure relates to compounds of formula (AI), (I), (AII), and (II), or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof, a pharmaceutical composition comprising a compound of formula (AI), (I), (AII), and (II), and use thereof, wherein R2, R3, R4, R5, R6, R7, R10, R11a, R11b, R12, R16, R19a, R19b, and R20 are described herein. Such compounds are envisioned useful for the prevention and treatment of a variety of CNS-related conditions, for example, treatment of sleep disorders, mood disorders, movement disorders, convulsive disorders, schizophrenin spectrum disorders, disorders of memory and / or cognition, personality disorders, autism spectrum disorders, pain, traumatic brain injury, vascular diseases, substance abuse disorders and / or withdrawal syndromes, or tinnitus etc.

Description

[0001] Citations to related applications [0002] This application claims the benefit of U.S. Provisional Application No. 62 / 792,243, filed January 14, 2019, the disclosure of which is hereby incorporated by reference in its entirety. Background technique [0003] The human brain comprises approximately 100 billion neurons forming an intricate network of myriad connections that evolve with inputs from the external and internal environment as well as physiological synapses, dendrites, and axons during brain maturation and throughout life. Sculpted by synapses, these neurons are constantly adapting and reconnecting themselves. Brain excitability is defined as the animal's level of arousal, on a continuum from coma to convulsions, and is regulated by various neurotransmitters. In general, neurotransmitters are responsible for regulating ionic conductance across nerve cell membranes. [0004] GABA A (gamma-aminobutyric acid) A The receptor is the major inhibitory neurotransmit...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/56A61K31/41A61K31/57C07D257/04
CPCA61P25/00C07J43/003A61K31/58A61K45/06
Inventor 李慧宋运涛
Owner BEIJING XUANYI PHARMASCIENCES CO LTD
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