Neuroactive steroids and methods of use thereof

a technology of neuroactive steroids and steroid receptors, applied in the field of neuroactive steroids, can solve the problems of significant loss of nmda potentiation, and achieve the effects of increasing the metabolic stability of these compounds, reducing the risk of adverse effects, and improving the effect of nmda potentiation

Inactive Publication Date: 2016-02-04
SAGE THERAPEUTICS
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0007]The inventors of the present invention, during an on-going exploration of Org-1 analogs for NMDA modulation, a portion of which is described in PCT / US2012 / 054261, incorporated herein by reference, discovered several specific combination of elements which provides NMDA modulators with comparatively superior properties. For example, as shown in Table 1, compounds bearing a beta-hydrogen at C5 are disfavored compared to compounds bearing either alpha-hydrogen C5 or double bond across C5-C6 due to loss of potentiation of the NMDA receptor. The removal of the methyl at C21 also results in significant loss of NMDA potentiation. Disubstitution at C3 is expected to increase metabolic stability of these compounds and is thus a preferrred feature of the invention. Fluorination on the C17 side chain has been shown to improve potency and limit maximum potentiation of the NMDA receptor when tested as high as 1 μM concentration of compound. A secondary or tertiary terminal alcohol on the C17 side chain has been shown to improve potency and limit maximum potentiation of the NMDA receptor when tested as high as 1 μM concentration of compound, and is thus a preferred feature of the invention, with a preference for bulkier groups at the terminating end containing 2-3 carbons, or a group comprising fluorine substitution. Such properties are expected limit the risk of inducing glutamate driven neurotoxicity relative to compounds that achieve a greater maximum potentiation of the NMDA receptor. Compounds of the present invention encompass various combinations of these specified features to provide superior NMDA modulators.

Problems solved by technology

The removal of the methyl at C21 also results in significant loss of NMDA potentiation.

Method used

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Examples

Experimental program
Comparison scheme
Effect test

example 1

[0212]

[0213]Preparation of Compound 1-2.

[0214]To a solution of ketone 1-1 (50.0 g, 0.17 mol) and ethylene glycol (62 mL) in toluene (600 mL) was added p-toluenesulfonic acid (1.4 g, 7.28 mmol). The reaction mixture was refluxed overnight with a Dean-Stark trap. The mixture was cooled to room temperature, diluted with ethyl acetate (500 mL), and washed with saturated aqueous sodium bicarbonate (300 mL×2) and brine (300 mL×2). The organic phase was dried over sodium sulfate and concentrated in vacuum to afford crude product 1-2 (64.0 g, 100%) which was directly used in the next step without further purification. 1H NMR: (400 MHz, CDCl3) δ 5.35 (d, J=5.6 Hz, 1H), 3.97-3.82 (m, 4H), 3.59-3.47 (m, 1H), 2.34-2.21 (m, 2H), 2.06-1.94 (m, 2H), 1.90-1.74 (m, 3H), 1.73-1.64 (m, 1H), 1.63-1.33 (m, 10H), 1.32-1.19 (m, 1H), 1.14-1.03 (m, 1H), 1.01 (s, 3H), 0.99-0.93 (m, 1H), 0.86 (s, 3H).

[0215]Preparation of Compound 1-3.

[0216]To a solution of compound 1-2 (32 g, 96 mmol) in dry CH2Cl2 (1200 mL) ...

example 2

[0241]

[0242]Preparation of 2-2.

[0243]To a solution of MAD (28.87 mmol, freshly prepared) in toluene (20 mL) was added dropwise a solution of 2-1 (4 g, 9.62 mmol) in toluene (20 mL) at −78° C. during a period of 1 h under nitrogen. Then the reaction mixture was stirred for 30 min, a solution of EtMgBr (29 mL, 28.87 mmol, 1.0 M in toluene) was added dropwise at −78° C. The reaction mixture was warmed to −40° C. and stirred at this temperature for 3 hours. TLC (petroleum ether:ethyl acetate=3:1) showed that the starting material was consumed completely. The mixture was poured into aqueous saturated NH4Cl solution (200 mL) and extracted with EtOAc (150 mL×2). The combined organic phases were dried over Na2SO4, and the solvent was evaporated to afford crude product. The crude product was purified by column chromatography on silica gel (eluent: petroleum ether:ethyl acetate=15:1) to give the product 2-2 (2.0 g, 47.6%) as white powder. 1H NMR: (400 MHz, CDCl3) δ 5.28 (d, J=5.2 Hz, 1H), 3.6...

example 3

[0271]

[0272]Preparation of 3-2.

[0273]To a suspension of 3-1 (400 mg, 1.035 mmol) and CsF (76 mg) in toluene / THF (20 mL, 8 / 1) was added TMSCF3 (1.53 mL, 10.35 mmol) and the mixture was stirred for 20° C. at room temperature under nitrogen. TLC (petroleum ether:ethyl acetate=3 / 1) showed the starting material was consumed completely. A solution of TBAF (6.8 mL, 1 M in THF) was added and the mixture was stirred for 4 h at room temperature. The mixture was diluted with MTBE (200 mL), washed with aq. saturated NaHCO3 solution (30 mL×3) and concentrated in vacuum. The residue was purified by column chromatography on silica gel (eluent: petroleum ether:ethyl acetate=20:1) to afford 3-2 (220 mg, 46%) as white solid. 1H NMR: (400 MHz, CDCl3) δ 5.31 (d, J=2.0 Hz, 1H), 2.44-2.41 (m, 1H), 2.04-1.96 (m, 3H), 1.81-1.67 (m, 5H), 1.65-1.39 (m, 11H), 1.34-1.32 (m, 3H), 1.31-1.25 (m, 1H), 1.21-1.10 (m, 3H), 1.12-0.98 (m, 4H), 0.96 (s, 3H), 0.98-0.90 (m, 4H), 0.68 (s, 3H.)

[0274]Preparation of 3-3 and 3...

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Abstract

(3alpha,3beta)-disubstituted 17beta steroidal compounds, pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof, are provided for the prevention and treatment of a variety of CNS-related conditions.

Description

RELATED APPLICATIONS[0001]The present application claim priority under 35 U.S.C. §119(e) to U.S. provisional patent application U.S. Ser. No. 61 / 779,735, filed Mar. 13, 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 as a result of neuronal action potentials. When released into the synaptic cleft, an excitatory chemical...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): C07J9/00
CPCC07J9/00C07J9/005C07J13/005C07J13/007C07J21/008C07J41/0061A61P1/14A61P23/00A61P25/00A61P25/04A61P25/08A61P25/14A61P25/16A61P25/18A61P25/20A61P25/22A61P25/24A61P25/28A61P25/30A61P27/16A61P29/00A61P3/04A61P43/00A61P9/00A61P9/10A61K31/575
Inventor MARTINEZ BOTELLA, GABRIELHARRISON, BOYD L.ROBICHAUD, ALBERT J.SALITURO, FRANCESCO G.
Owner SAGE THERAPEUTICS
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