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Neuroactive steroids, compositions, and uses thereof

a technology of compositions and neuroactive steroids, applied in the field of neuroactive steroids, compositions, can solve the problems that progesterone is not consistently effective in the treatment of the aforementioned syndromes, and achieve the effects of reducing or avoiding symptoms or causes of disease, and reducing or minimizing one or more symptoms

Inactive Publication Date: 2016-06-02
SAGE THERAPEUTICS
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The patent text is about the amount of a compound that is needed to treat a disease or condition. It means the amount of the compound that will provide a therapeutic benefit, either alone or in combination with other therapies. This can include improving overall therapy, reducing or avoiding symptoms or causes of the disease, or enhancing the effectiveness of another therapeutic agent.

Problems solved by technology

However, progesterone is not consistently effective in the treatment of the aforementioned syndromes.

Method used

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  • Neuroactive steroids, compositions, and uses thereof
  • Neuroactive steroids, compositions, and uses thereof
  • Neuroactive steroids, compositions, and uses thereof

Examples

Experimental program
Comparison scheme
Effect test

example 1

Synthesis of Compounds 1 and 2

[0248]Synthesis of A1 and A2 Intermediates

[0249]Synthesis of Compounds 1 and 2

[0250]To a solution of 006-1, dehydroepiandrosterone (11 g, 38.17 mmol) in EtOH (150 mL) was added 10% Pd / C (1.1 g). Then the mixture was stirred under H2 (40 psi) at 40° C. for 12 hours. TLC showed the starting material was consumed completely. The mixture was filtered and the filtrate was concentrated under vacuum to give 008-1 (11 g, 99%) as a white solid. 1H NMR (008-1): (400 MHz, CDCl3) δ 3.59-3.51 (m, 1H), 2.46-2.39 (m, 1H), 2.10-2.01 (m, 1H), 1.92-1.81 (m, 1H), 1.80-0.94 (m, 19H), 0.85 (s, 3H), 0.82 (s, 3H), 0.69-0.62 (m, 1H).

[0251]To a solution of 008-1 (11 g, 37.8 mmol) in dry pyridine (150 mL) was added p-TsCl (11.4 g, 68.2 mmol) in portions. The mixture was stirred at 40° C. for 6 hours. Water was added slowly, then a white solid precipitated. The white solid was filtered, and washed with aqueous HCl (200 mL*3, 1M), followed by water (200 mL*3). The solid was dried ...

example 2

Synthesis of Compounds 3 and 38

[0256]

[0257]To a solution of 001-1 (20 g, 55 mmol) in pyridine (200 mL) was added dropwise Ac2O (8.45 g, 82.8 mmol), then the mixture was stirred at room temperature over night. TLC (petroleum ether:ethyl acetate=1:1) showed that the starting material was consumed completely. The mixture was poured into water (1.5 L) with stirring. The resulting solid was collected by filtration and washed with 500 mL of HCl (1 M), followed by water (500 mL×3). The solid was dried by lyophilization, and 001-2 (19.1 g, 85.9%) was obtained as a white solid. 1H NMR (001-2): (400 MHz, CDCl3) δ 5.68 (s, 1H), 5.03 (d, J=17.6 Hz, 1H), 4.84 (d, J=17.6 Hz, 1H), 4.48-4.47 (m, 1H), 2.81-2.77 (m, 1H), 2.57-2.20 (m, 5H), 2.17 (s, 3H), 2.17-1.97 (m, 3H), 1.91-1.79 (m, 2H), 1.76-1.64 (m, 2H), 1.54-1.46 (m, 2H), 1.42 (s, 3H), 1.30-1.07 (m, 3H), 0.98 (s, 3H), 0.90-0.89 (m, 1H).

[0258]To a solution of 001-2 (17 g, 42 mmol) in EtOH (19 mL) and THF (190 mL) was added CH(OEt)3 (38.6 mL, 231...

example 3

Synthesis of Compounds 47 and 48

[0268]Synthesis of Intermediates 039-1 and 051-1

[0269]Synthesis of Compounds 47 and 48

[0270]To a solution of the mixture of 008-4 and 008-4A (2.5 g, 8.68 mmol) in EtOH (75 mL) was added H2SO4 (10 drops, 98%). The mixture was stirred at 20° C. for 3 h. TLC showed the starting material was consumed completely. The mixture was quenched with aqueous NaHCO3 (40 mL). The mixture was extracted with EtOAc (100 mL×2) and washed with aqueous NaCl (50 mL). The organic phase was dried over Na2SO4 and evaporated to give the crude product, which was purified by column chromatography on silica gel (ethyl acetate: petroleum ether=1:2) to afford the mixture of 039-1 and 051-1 (1.8 g, 60%) as a white solid.

[0271]To a solution of t-BuOK (1.47 g, 13.16 mmol) in t-BuOH (10 mL) was added a solution of 039-1 (440 mg, 1.32 mmol) in 1,2-dimethoxyethane (4 mL) dropwise at room temperature. Then a solution of TosMic (1.0 g, 5.1 mmol) in 1,2-dimethoxyethane (6 mL) was added drop...

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Abstract

Described herein are neuroactive steroids of the Formula (I): (Formula (I)) or a pharmaceutically acceptable salt thereof; wherein R1a and R1b are as defined herein. Such compounds are envisioned, in certain embodiments, to behave as GABA modulators. The present invention also provides pharmaceutical compositions comprising a compound of the present invention and methods of use and treatment, e.g., such for inducing sedation and / or anesthesia.

Description

RELATED APPLICATIONS[0001]The present application claims priority under 35 U.S.C. §119(e) to U.S. provisional patent application, U.S. Ser. No. 61 / 856,592, filed Jul. 19, 2013, which is incorporated herein by reference.BACKGROUND OF THE INVENTION[0002]Brain excitability is defined as the level of arousal of an animal, a continuum that ranges from coma to convulsions, and is regulated by various neurotransmitters. In general, neurotransmitters are responsible for regulating the conductance of ions across neuronal membranes. At rest, the neuronal membrane possesses a potential (or membrane voltage) of approximately −70 mV, the cell interior being negative with respect to the cell exterior. The potential (voltage) is the result of ion (K+, Na+, Cl−, organic anions) balance across the neuronal semipermeable membrane. Neurotransmitters are stored in presynaptic vesicles and are released under the influence of neuronal action potentials. When released into the synaptic cleft, an excitator...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): C07J41/00
CPCC07J41/0094A61K45/06A61K31/56A61K31/565A61K31/567C07J1/0011C07J1/0022C07J5/0053C07J11/00C07J21/008C07J31/006C07J51/00C07J71/001A61P21/02A61P23/00A61P25/00A61P25/08A61P25/20A61P43/00A61K2300/00C07J3/00
Inventor BOTELLA, GABRIEL MARTINEZHARRISON, BOYD L.ROBICHAUD, ALBERT JEANSALITURO, FRANCESCO GERALD
Owner SAGE THERAPEUTICS
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