Neuroactive steroids, compositions, and uses thereof

a technology of neuroactive steroids and compositions, 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

Inactive Publication Date: 2016-08-11
SAGE THERAPEUTICS
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0011]Provided herein are C21-substituted neuroactive steroids designed, for example, to act as GABA modulators. In certain embodiments, such compounds are envisioned to be useful as therapeutic agents for the inducement of anesthesia and / or sedation in a subject. In some embodiments, such compounds are envisioned to be useful as therapeutic agents for treating a CNS-related disorder (e.g., sleep disorder, a mood disorder, a schizophrenia spectrum disorder, a convulsive disorder, a disorder of memory and / or cognition, a movement disorder, a personality disorder, autism spectrum disorder, pain, traumatic brain injury, a vascular disease, a substance abuse disorder and / or withdrawal syndrome, or tinnitus) in a subject in need (e.g., a subject with Rett syndrome, Fragile X syndrome, or Angelman syndrome).

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

General Procedure A: Preparation of A / B-Trans Scaffolds

[0234]

Step 1. Preparation of Compound A2.

[0235]Finely-ground potassium hydroxide (28.0 g, 165 mmol) was added to a solution of commercially available 19-hydroxyandrost-4-ene-3,17-dione (A1, 50.0 g, 165 mmol) in anhydrous 1,2-dimethoxyethane (500 mL) at 0° C. under nitrogen, after which methyl sulfate (43.7 g, 208 mmol) was added portionwise. The mixture was slowly warmed to room temperature, stirring for a total of 18 h, at which point TLC analysis of the mixture (7:3 hexanes / ethyl acetate) indicated completion of the reaction. The mixture was diluted with water (500 mL) and extracted with ethyl acetate (3×200 mL). The combined organic extracts were washed with saturated aqueous sodium chloride solution (100 mL), dried with anhydrous sodium sulfate and filtered. The solvents were removed under reduced pressure and the residue was purified by column chromatography on silica gel, eluting with heptane / ethyl acetate (2:1), to provid...

example 2

General Procedure A: Preparation of A / B-Trans Scaffolds

[0245]

Step 1. Preparation of Compound A12.

[0246]Prepared according General Procedure A, Step 1 from A1, 10.0 g, 33 mmol) and ethyl sulfate (17.3 mL, 132 mmol), with purification by column chromatography on silica gel to provide compound A12 as a yellow oil (4.6 g, 42%).

Step 2. Preparation of Compound A13.

[0247]Prepared according General Procedure A, Step 2 from compound A12 (4.6 g, 14 mmol) to provide crude compound A13 as a yellow oil that was used in the next step without further purification.

Step 3. Preparation of Compound A14.

[0248]Prepared according General Procedure A, Step 3 from crude compound A13, with purification by column chromatography on silica gel to provide compound A14 as a yellow oil (1.5 g, 31%).

Step 4. Preparation of Compound A15.

[0249]Prepared according General Procedure A, Step 4 from compound A14 (1.7 g, 5.1 mmol) to provide crude compound A15 as a yellow oil that was used in the next step without further ...

example 3

General Procedure B: Preparation of A / B-Trans Scaffold C-21 Analogs

[0256]

[0257]5-Chloro-1H-benzo[d][1,2,3]triazole (470 mg, 3.06 mmol) and potassium carbonate (704 mmol) 5.1 mmol) were added to a solution of compound A11 (225 mg, 0.51 mmol) in anhydrous tetrahydrofuran (20 mL) at room temperature under nitrogen and the mixture was stirred for 16 h, at which point TLC analysis of the mixture (2:1 hexanes / ethyl acetate) indicated completion of the reaction. The mixture was diluted with water (120 mL) and extracted with ethyl acetate (3×100 mL). The combined organic extracts were washed with saturated aqueous sodium chloride solution (60 mL), dried with sodium sulfate and filtered. The solvents were removed under reduced pressure and the residue was semi-purified by column chromatography on silica gel, eluting with hexanes / ethyl acetate (3:1), to provide a mixture of the three regioisomers. The residue was further purified by reverse phase preparative HPLC to provide 35 as an off-white...

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Abstract

Described herein are neuroactive steroids of the Formula (I): or a pharmaceutically acceptable salt thereof; wherein -------, R1, R2, R5, A and L 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 applications, U.S. Ser. No. 61 / 869,440 filed Aug. 23, 2013, U.S. Ser. No. 61 / 869,446 filed Aug. 23, 2013, and U.S. Ser. No. 62 / 014,018 filed Jun. 18, 2014, each of which are 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 releas...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): C07J43/00
CPCC07J43/003A61K31/58A61K45/06C07J1/0059C07J7/002C07J7/007C07J7/0085C07J13/007C07J21/00C07J21/008A61P23/00A61P25/00A61P25/04A61P25/08A61P25/18A61P25/20A61P25/24A61P25/28A61P25/30A61P25/36A61P27/16A61P29/02A61P9/00A61K2300/00
Inventor MARTINEZ BOTELLA, GABRIELHARRISON, BOYD L.ROBICHAUD, ALBERT JEANSALITURO, FRANCESCO GERALDHERR, ROBERT JASONKARGBO, ROBERT BORBO
Owner SAGE THERAPEUTICS
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