3,3 disubstituted 19-nor pregnane compounds, compositions, and uses thereof

a technology compound, which is applied in the field of disubstituted 19-nor pregnane compounds, compositions, and compositions, can solve the problems that progesterone is not consistently effective in the treatment of the aforementioned syndrome, and achieve the effects of preventing further metabolism, reducing the potential for oxidation to ketone, and reducing the risk of side effects

Inactive Publication Date: 2015-10-15
SAGE THERAPEUTICS
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0011]The present invention is based, in part, on the desire to provide novel 19-nor compounds with good potency, pharmacokinetic (PK) properties, oral bioavailability, formulatability, stability, safety, clearance and / or metabolism. One key feature of the compounds as described herein is disubstitution at the C3 position. The inventors envision disubstitution at C-3 will eliminate the potential for oxidation to the ketone, prevent further metabolism, and reduce the potential for secondary elimination pathways, such as glucuronidation. The inventors further envision the overall effect of C3 disubstitution should be of improving the overall PK parameters and reducing potential toxicities and side effects, which may allow, in certain embodiments, administration orally and / or chronically. Another key feature of the compounds as described herein is the presence of a hydrogen at the C10 position (“19-nor”) rather than a methyl group. The inventors envision 19-nor compounds, as compared to their C10-methyl counterparts, will have improved physical properties, such as improved solubility. The inventors envision further enhancement of solubility, for example, when the AB ring system is in the cis configuration.

Problems solved by technology

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

Method used

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  • 3,3 disubstituted 19-nor pregnane compounds, compositions, and uses thereof
  • 3,3 disubstituted 19-nor pregnane compounds, compositions, and uses thereof
  • 3,3 disubstituted 19-nor pregnane compounds, compositions, and uses thereof

Examples

Experimental program
Comparison scheme
Effect test

example 1

Synthesis of Compounds 8a / b, 9a / b, and 10a / b

[0358]

[0359]Synthesis of Compound 2.

[0360]Compound 1 (500 mg, 1.84 mmol) and 10% Pd / C (20 mg) in tetrahydrofuran (5 mL) and concentrated hydrobromic acid (0.02 mL) was hydrogenated with a hydrogen balloon. After stirring at room temperature for 24 h, the mixture was filtered through a pad of celite and the filtrate was concentrated in vacuo. Recrystallization from acetone to give compound 2 (367 mg, 1.34 mmol, 73%). 1H NMR (400 MHz, CDCl3), δ (ppm), 2.61-2.54 (m, 1H), 0.98 (S, 3H).

[0361]Synthesis of Compound 3.

[0362]To a solution of compound 2 (274 mg, 1 mmol) in methanol (4 mL) was added iodine (0.1 mmol). After stirring at 60 OC for 12 h, TLC showed no SM and the solvent was removed in vacuo. The crude product was dissolved in dichloromethane (20 mL) and washed with saturated NaHCO3 (15 mL), brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by chromatography on basic alumina (petroleum ether / ethyl acetate=9:1...

example 2

Synthesis of compounds 14a / b, 15a / b, and 16a / b

[0385]

[0386]Synthesis of Compound 11a and 11b.

[0387]To a solution of compound 5 (800 mg, 2.79 mmol) and PhSO2CF2H (540 mg, 2.79 mmol) in THF (25 mL) and HMPA (0.5 mL) at −78° C. under N2 was added LHMDS (4 mL, 1M in THF) dropwise. After stirring at −78° C. for 2 h, the reaction mixture was quenched with saturated aqueous NH4Cl solution (10 mL) and allowed to warm to room temperature then extracted with Et2O (20 mL×3). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrate. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate=10 / 1) to give the mixture of compound 11a and 11b (700 mg). The mixture was further purified by chiral-HPLC to afford compound 11a (200 mg, t=4.31 min).

[0388]1H NMR (400 MHz, CDCl3), δ (ppm), 7.99-7.97 (d, 2H, J=7.6 Hz), 7.77-7.75 (m, 1H), 7.64-7.60 (m, 2H), 5.14-5.08 (m, 1H), 0.88 (s, 3H); compound 11b (260 mg, t=5.66 min). 1H N...

example 3

Synthesis of 6-difluoro Analogs

[0429]

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Abstract

Provided herein are 3,3-disubstituted 19-nor-steroidal compounds according to Formula (I) and (III): where R1, R2, R3, R3′, R4, R6a, R6a, R11a, and R11b are as defined herein. Compounds of the present invention are contemplated useful for the prevention and treatment of a variety of CNS-related conditions, for example, treatment of sleep disorders, mood disorders, insomnia, anxiety, depression, traumatic brain injury (TBI), stress, and epilepsy.

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 / 547,291, filed Oct. 14, 2011 and U.S. Ser. No. 61 / 698,204, filed Sep. 7, 2012, each of 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 poten...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): C07J43/00C07J9/00C07J5/00C07J7/00
CPCC07J43/003C07J7/008C07J9/005C07J5/0015C07J7/002C07J7/0085C07J31/006A61P25/00A61P25/04A61P25/08A61P25/14A61P25/16A61P25/18A61P25/20A61P25/22A61P25/24A61P25/28A61P27/16A61P9/10
Inventor UPASANI, RAVINDRA B.ASKEW, JR., BENNY C.HARRISON, BOYD L.DISTEFANO, PETER SCOTTSALITURO, FRANCESCO G.ROBICHAUD, ALBERT J.
Owner SAGE THERAPEUTICS
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