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Neuroactive steroids, compositions, and uses thereof

A compound, unsubstituted technology, used in the preparation of steroids, drug combinations, steroids, etc., and can solve problems such as changes in the degree of regulation

Active Publication Date: 2014-07-30
SAGE THERAPEUTICS
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

NMDA receptors are positively modulated by PS; however, the degree of modulation varies considerably

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

Embodiment 1

[0532] Embodiment 1. Preparation of Compound ST-200-A-001

[0533]

[0534]

[0535] Preparation of compound 2: To a solution of ketone 1 (50.0 g, 0.17 mol, 1.0 eq) and ethylene glycol (62 mL) in toluene (600 mL) was added p-toluenesulfonic acid (1.4 g, 7.28 mmol). The reaction mixture was heated at reflux overnight using a Dean-Stark trap. LCMS showed complete consumption of starting material. 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 vacuo to obtain crude product 2 (64.0 g, 100%), which was directly used in the next step without further purification. 1 H NMR: (400MHz, CDCl3 )δ5.35(d, J=5.6Hz, 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...

Embodiment 2

[0545] Embodiment 2. Preparation of Compound ST-200-A-003

[0546]

[0547] Preparation of compound A_003_1: at 0°C in N 2 Down to Ph 3 A solution of PEtBr (12.25 g, 33.00 mmol, 10.0 eq) in dry THF (15 mL) was added dropwise to a solution of t-BuOK (3.70 g, 33.00 mmol, 10.0 eq) in dry THF (10 mL). The mixture was stirred at room temperature for 1.5 hours. A solution of INTA (1.00 g, 3.31 mmol, 1.0 eq) in THF (10 mL) was then added dropwise and the resulting mixture was stirred at 70°C for 4 hours. TLC (PE:EA=3:1) indicated complete consumption of starting material. The reaction was saturated with NH 4 Aqueous Cl solution (50 mL) was quenched and extracted with EA (30 mL x 2). Pass the combined organic phases through Na 2 SO 4 Dry and concentrate in vacuo. The residue was purified by column chromatography on silica gel (eluent: PE:EA=12:1) to give the product (900 mg, 90.9%) as a white powder. 1 H NMR: (400MHz, CDCl 3 )δ5.32(d, J=5.2Hz, 1H), 5.15-5.12(m, 1H), 2.44-2....

Embodiment 3

[0551] Example 3. Preparation of Compound ST-200-A-007

[0552]

[0553] Preparation of Compound INT E: To a solution of 9-BBN (0.5M in THF, 133mL, 66.6mmol, 10.0eq) was added dropwise A_001_1 (2.0g, 6.66mmol, 1.0eq) in THF (10mL) under ice bath The solution. The reaction mixture was heated to 60 °C and stirred for 20 hours. The mixture was cooled to 0 °C and 10% aqueous NaOH (20 mL) was added followed by 30% H 2 o 2 Aqueous solution (30%, 10 mL). The mixture was stirred at 0 °C for 2 hours, then extracted with EA (30 mL x 3). The combined organic layers were washed with brine (30 mL), passed through Na 2 SO 4 Drying and concentration in vacuo gave the crude product, which was purified by flash column chromatography eluting with PE / EA (10 / 1 ) to afford INT E (1.0 g, 47%) as a white solid. 1 H NMR: (400MHz, CDCl 3 )δ5.30 (d, J=5.2Hz, 1H), 3.75-3.71 (dd, J 1 =10.4Hz,J 2 =6.8Hz, 1H), 3.58-3.53 (dd, J 1 =10.4Hz,J 2 =7.6Hz, 1H), 2.43-2.41(d, J=10.4Hz, 1H), 2.02-1.96(...

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Abstract

Compounds are provided according to Formula (I) and pharmaceutically acceptable salts thereof, wherein Z is a group of the formula (i), (ii), (iii), (iv), or (v), and wherein L1, L2, L3, X1, X2, Y, Rz4, Rz5, Rz6, n, R1, R2, R3a, R3b, R4a, R4b, R6a, R6b, R7a, R7b, R11a, R11b, R14, R17, R19, R20, R23a, R23b, and R24 are as defined herein, and pharmaceutical compositions thereof. Compounds of the present invention are contemplated useful for the prevention and treatment of a variety of CNS-related conditions in mammals.

Description

[0001] related application [0002] This application claims priority under 35 U.S.C. §119(e) to U.S. Provisional Patent Application U.S.S.N. 61 / 532,427, filed September 8, 2011, which is incorporated herein by reference. Background technique [0003] Brain excitability is defined as the animal's level of arousal (ranging on a continuum from coma to convulsions) and is modulated by various neurotransmitters. In general, neurotransmitters are responsible for regulating the conductance of ions across neuronal membranes. At rest, the neuronal membrane has an electrical potential (or membrane voltage) of about -70 mV, negative inside the cell relative to the outside of the cell. The electric potential (voltage) is the ion (K + 、Na + , Cl - , organic anions) balance results. Neurotransmitters are stored in presynaptic vesicles and released as a result of neuronal action potentials. When released into the synaptic cleft, excitatory chemical transmitters such as acetylcholine wi...

Claims

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Application Information

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IPC IPC(8): C07J41/00C07J31/00C07J9/00A61K31/57A61K31/575A61P25/18A61P25/28
CPCC07J1/00C07J1/0029C07J3/00C07J7/007C07J9/00C07J9/005C07J31/003C07J31/006C07J41/00C07J41/0005C07J41/0011C07J41/0055C07J43/003A61P25/00A61P25/04A61P25/08A61P25/14A61P25/16A61P25/18A61P25/20A61P25/22A61P25/24A61P25/28A61P25/30A61P25/32A61P25/36A61P27/16A61P43/00A61P9/10A61K31/57A61K31/575C07J31/00C07J75/00
Inventor R.B.厄帕萨尼B.L.哈里森小本尼.C.阿斯丘J-C.多达特F.G.萨里特罗A.J.罗比肖
Owner SAGE THERAPEUTICS
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