Organic compounds

Abstract

The invention relates to particular prodrugs and analogs of (3 alpha,5 alpha)-3-hydroxy-21-(1H-imidazol-1-yl)-3-methoxymethyl)-pregnan-20-one, in free or pharmaceutically acceptable salt and / or substantially pure form as described herein, pharmaceutical compositions thereof, and methods of use as sedatives, hypnotics, anxiolytics, and / or anesthetics, and methods for treatment of depression, anxiety, insomnia, epilepsy, and other central nervous system disorders, as well as to combinations with other agents.

Description

[0001] Cross References to Related Applications

[0002] This application is an international application claiming priority to and benefit of U.S. Provisional Application No. 62 / 780,703, filed December 17, 2018, the contents of which are hereby incorporated by reference in their entirety.

[0003] field of invention

[0004] The present invention relates to (3α,5α)-3-hydroxy-21-(1H-imidazol-1-yl)-3-methoxy as described herein in free or pharmaceutically acceptable salt and / or in substantially pure form Certain prodrugs and analogues of methyl)-pregnane-20-one, pharmaceutical compositions thereof, methods of use as sedatives, hypnotics, anxiolytics and / or anesthetics, in the treatment of depression, anxiety, insomnia, epilepsy and others Methods for disorders of the central nervous system, and combinations with other drugs.

[0005] Background of the invention

[0006] Brain excitability, defined as the animal's level of arousal (a continuum from coma to convulsions), is regul...

Examples

preparation example Construction

[0161] 3α-Hydroxy-3β-methoxymethyl-5α-pregnane-20-one can be synthesized from (3R)-spiro[oxirane-2α,5α-pregnane]-20-one and sodium methoxide such as Hogenkamp et al. People, "Synthesis and in Vitro Activity of 3β-Substituted-3α-hydroxypregnan-20-ones: Allosteric Modulators of the GABA A Prepared as described in Receptor"J Med.Chem.40:61-72 (1997). 21-substituted steroids can be prepared from the corresponding 21-bromosteroids using catalytic Br in MeOH of HBr 2Synthesized from 20-keto steroids. Other sources of useful synthetic methods include: Botella et al., J. Med Chem., 48:3500-3511 (2015); Botella et al., J. Med Chem., 60:7810-7819 (2017); Wong et al. , Steroids 71:77-82 (2006); Botella et al., WO 2016 / 061527; Hogenkamp, ​​Derek L., WO 2000 / 66614; Goliber et al., US 2006 / 0074059; Chang et al., WO 2005 / 105822; Woodward, Richard M., WO 2006 / 131392; the contents of each of the aforementioned documents are hereby incorporated by reference in their entirety. In general, co...

Embodiment 1

[0164] Example 1: Synthesis of 3α-hydroxyl-21-(1′-imidazolyl)-3β-methoxymethyl-5α-pregnane-20-one (compound of formula A)

[0165]

[0166] Step 1: 21-Bromo-3α-hydroxy-3β-methoxymethyl-5α-pregnane-20-one

[0167] To a stirred solution of 3α-hydroxy-3β-methoxymethyl-5α-pregna-20-one (30.0 g, 82.9 mmol) in 900 mL methanol at room temperature was added 3 drops of 48% HBr in water. A solution of bromine (13.9 g, 87.1 mmol) in 200 mL of methanol was then added dropwise over 2 hours, during which time the reaction was protected from light. After TLC (1% acetone / dichloromethane) indicated the absence of starting material and the formation of a less polar product, the reaction was concentrated to about 300 mL. Then add CH 2 Cl 2 (400 mL), the reactant was poured into a separatory funnel containing 200 mL of water. Separate the phases and wash the aqueous phase with CH 2 Cl 2 (3 x 100 mL) extraction. Combine the organic phases and wash with 200 mL saturated NaHCO 3 Washed wi...

Embodiment 2

[0170] Example 2: 1-((3R,5S,8R,9S,10S,13S,14S,17S)-3-hydroxyl-3-(methoxymethyl)-10,13-dimethylhexadecahydro- 1H-Cyclopentadien[a]phenanthrene-17-yl)-2-(1H-imidazol-1-yl-d3)ethan-1-one

[0171] imidazole-d 4 (0.193g, 2.72mmol, 3.0eq) To a 0°C solution in THF (2mL) was added lithium hydride (0.0237g, 2.8mmol, 3.1eq). The solution was stirred at 0 °C under Ar for 2 h. To the reaction mixture was slowly added 21-bromo-3α-hydroxy-3β-methoxymethyl-5α-pregnane-20-one (0.40 g , 0.906mmol, 1.0 equivalent). After stirring at 0 °C for 3 hours, the reaction mixture was quenched with methanol in an ice bath. The organic layer was separated and concentrated under reduced pressure. The residue was further purified by column chromatography to afford the pure title compound (0.184 g, 0.426 mmol) as a white powder in 50% isolated yield. 1 H NMR (500MHz, chloroform-d) δ4.86–4.60 (m, 2H), 3.41 (s, 3H), 3.20 (s, 2H), 2.60 (t, J=8.9Hz, 1H), 2.31–2.12 ( m,1H),2.06–1.90(m,1H),1.84–1.66(m,4H)...

[0001] Cross References to Related Applications

[0002] This application is an international application claiming priority to and benefit of U.S. Provisional Application No. 62 / 780,703, filed December 17, 2018, the contents of which are hereby incorporated by reference in their entirety.

[0003] field of invention

[0004] The present invention relates to (3α,5α)-3-hydroxy-21-(1H-imidazol-1-yl)-3-methoxy as described herein in free or pharmaceutically acceptable salt and / or in substantially pure form Certain prodrugs and analogues of methyl)-pregnane-20-one, pharmaceutical compositions thereof, methods of use as sedatives, hypnotics, anxiolytics and / or anesthetics, in the treatment of depression, anxiety, insomnia, epilepsy and others Methods for disorders of the central nervous system, and combinations with other drugs.

[0005] Background of the invention

[0006] Brain excitability, defined as the animal's level of arousal (a continuum from coma to convulsions), is regul...

Examples

preparation example Construction

[0161] 3α-Hydroxy-3β-methoxymethyl-5α-pregnane-20-one can be synthesized from (3R)-spiro[oxirane-2α,5α-pregnane]-20-one and sodium methoxide such as Hogenkamp et al. People, "Synthesis and in Vitro Activity of 3β-Substituted-3α-hydroxypregnan-20-ones: Allosteric Modulators of the GABA A Prepared as described in Receptor"J Med.Chem.40:61-72 (1997). 21-substituted steroids can be prepared from the corresponding 21-bromosteroids using catalytic Br in MeOH of HBr 2Synthesized from 20-keto steroids. Other sources of useful synthetic methods include: Botella et al., J. Med Chem., 48:3500-3511 (2015); Botella et al., J. Med Chem., 60:7810-7819 (2017); Wong et al. , Steroids 71:77-82 (2006); Botella et al., WO 2016 / 061527; Hogenkamp, ​​Derek L., WO 2000 / 66614; Goliber et al., US 2006 / 0074059; Chang et al., WO 2005 / 105822; Woodward, Richard M., WO 2006 / 131392; the contents of each of the aforementioned documents are hereby incorporated by reference in their entirety. In general, co...

Embodiment 1

[0164] Example 1: Synthesis of 3α-hydroxyl-21-(1′-imidazolyl)-3β-methoxymethyl-5α-pregnane-20-one (compound of formula A)

[0165]

[0166] Step 1: 21-Bromo-3α-hydroxy-3β-methoxymethyl-5α-pregnane-20-one

[0167] To a stirred solution of 3α-hydroxy-3β-methoxymethyl-5α-pregna-20-one (30.0 g, 82.9 mmol) in 900 mL methanol at room temperature was added 3 drops of 48% HBr in water. A solution of bromine (13.9 g, 87.1 mmol) in 200 mL of methanol was then added dropwise over 2 hours, during which time the reaction was protected from light. After TLC (1% acetone / dichloromethane) indicated the absence of starting material and the formation of a less polar product, the reaction was concentrated to about 300 mL. Then add CH 2 Cl 2 (400 mL), the reactant was poured into a separatory funnel containing 200 mL of water. Separate the phases and wash the aqueous phase with CH 2 Cl 2 (3 x 100 mL) extraction. Combine the organic phases and wash with 200 mL saturated NaHCO 3 Washed wi...

Embodiment 2

[0170] Example 2: 1-((3R,5S,8R,9S,10S,13S,14S,17S)-3-hydroxyl-3-(methoxymethyl)-10,13-dimethylhexadecahydro- 1H-Cyclopentadien[a]phenanthrene-17-yl)-2-(1H-imidazol-1-yl-d3)ethan-1-one

[0171] imidazole-d 4 (0.193g, 2.72mmol, 3.0eq) To a 0°C solution in THF (2mL) was added lithium hydride (0.0237g, 2.8mmol, 3.1eq). The solution was stirred at 0 °C under Ar for 2 h. To the reaction mixture was slowly added 21-bromo-3α-hydroxy-3β-methoxymethyl-5α-pregnane-20-one (0.40 g , 0.906mmol, 1.0 equivalent). After stirring at 0 °C for 3 hours, the reaction mixture was quenched with methanol in an ice bath. The organic layer was separated and concentrated under reduced pressure. The residue was further purified by column chromatography to afford the pure title compound (0.184 g, 0.426 mmol) as a white powder in 50% isolated yield. 1 H NMR (500MHz, chloroform-d) δ4.86–4.60 (m, 2H), 3.41 (s, 3H), 3.20 (s, 2H), 2.60 (t, J=8.9Hz, 1H), 2.31–2.12 ( m,1H),2.06–1.90(m,1H),1.84–1.66(m,4H)...

Images