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Dihydrotetrabenazines and pharmaceutical compositions containing them.

A technology of dihydrotetrabenazine and dihydrobutadiene, applied in the field of dihydrotetrabenazine isomers, can solve problems such as unstable tetrabenazine and biological activity of unpublished compounds

Inactive Publication Date: 2007-06-13
BIOVAIL LAB INT BARBADOS
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0019] So far, as far as the applicant is aware, the RS and SR isomers derived from unstable tetrabenazine have not been separated (hereinafter individually or collectively referred to as cis-tetrabenazine, because the 3 and 11b position hydrogen atoms have cis-tetrabenazine The dihydrotetrabenazine isomers of formula relative orientation) were characterized and characterized, and the biological activity of these compounds has not been published so far

Method used

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  • Dihydrotetrabenazines and pharmaceutical compositions containing them.
  • Dihydrotetrabenazines and pharmaceutical compositions containing them.
  • Dihydrotetrabenazines and pharmaceutical compositions containing them.

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0132] Preparation of 2S, 3S, 11bR and 2R, 3R, 11bS Isomers of Dihydrotetrabenazine 1A. Reduced RR / SS Tetrabenazine

[0133]

[0134] 1M L-Selectride in tetrahydrofuran (135ml, 135mmol, 2.87eq) was dissolved at 0°C over 30 minutes  To a stirred solution of tetrabenazine RR / SS racemate (15 g, 47 mmol) in ethanol (75 ml) and tetrahydrofuran (75 ml) was added slowly. The mixture was stirred at 0 °C for 30 min after complete addition and then allowed to warm to room temperature.

[0135] The mixture was poured onto crushed ice (300g) and water (100ml) was added. The solution was extracted with diethyl ether (2 x 200ml) and the combined ethereal extracts were washed with water (100ml) and partially dried over anhydrous potassium carbonate. Drying was completed with anhydrous magnesium sulfate, and after filtration, the solvent was removed under reduced pressure (protected from light, bath temperature <20°C) to obtain a pale yellow solid.

[0136] The solid was slurried w...

Embodiment 2

[0164] Preparation of 2R, 3S, 11bR and 2S, 3R, 11bS Isomers of Dihydrotetrabenazine 2A. Preparation of 2,3-dihydrotetrabenazine

[0165] According to the method of embodiment 1A, use L-Selectride  Reduction of a THF solution containing a racemic mixture of RR and SS tetrabenazine enantiomers (15 g, 47 mmol) afforded a mixture of 2S, 3R, 11bR and 2R, 3S, 11bS enantiomers of dihydrotetrabenazine (12 g , 80%), as a white powdery solid. Then according to the method of embodiment 1B, with PCl 5 Dehydration of the partially purified dihydrotetrabenazine afforded a semi-purified mixture of the 11bR and 11bS isomers of 2,3-dihydrotetrabenazine (the 11bR enantiomers are not shown below) (12.92 g, 68% ), as a yellow solid.

[0166]

[0167] 2B. Epoxidation of the Crude Olefin from Example 2A

[0168]

[0169] A solution of 70% perchloric acid (3.70ml, 43mmol) in methanol (215ml) was added to a stirred solution of the crude olefin from Example 2A (12.92g, 42.9mmol) in me...

Embodiment 3

[0203] Alternative Methods for the Preparation of Isomer B and the Preparation of the Mesylate Salt

[0204] 3A. Reduced RR / SS Tetrabenazine

[0205]

[0206] 1M Selectride in tetrahydrofuran (52ml, 52mmol, 1.1 equivalents) was added in 30 minutes  To a cooled (ice bath), stirred solution of tetrabenazine racemate (15 g, 47 mmol) in tetrahydrofuran (56 ml) was added slowly. After the addition was complete, the mixture was allowed to warm to room temperature and stirred for an additional 6 hours. TLC analysis (silica, ethyl acetate) showed very little starting material remaining.

[0207] The mixture was poured into a stirred mixture of crushed ice (112g), water (56ml) and glacial acetic acid (12.2g). The resulting yellow solution was washed with diethyl ether (2 x 50ml) and basified by the slow addition of solid sodium carbonate (ca. 13g). Pet-ether (30-40°C) (56ml) was added to the mixture with stirring and the crude product β-DHTBZ was collected by filtration as ...

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Abstract

The invention provides novel isomers of dihydrotetrabenazine, individual enantiomers and mixtures thereof wherein the dihydrotetrabenazine is a 3,11 b-cis- dihydrotetrabenazine. Also provided are methods for the preparation of the novel isomers, pharmaceutical compositions containing them and their use in treating hyperkinetic movement disorders such as Huntington's disease, hemiballismus, senile chorea, tic, tardive dyskinesia and Tourette's syndrome.

Description

[0001] The present invention relates to novel dihydrotetrabenazine isomers, pharmaceutical compositions containing them, processes for their preparation and their therapeutic use. Background of the invention [0002] Tetrabenazine (chemical name: 1,3,4,6,7,11b-hexahydro-9,10-dimethoxy-3-(2-methylpropyl)-2H-benzo(a)quinone oxazin-2-ones) have been used as medicines since the late 1950s. Tetrabenazine was originally used as an antipsychotic and is now used to treat hyperkinetic movement disorders such as Huntington's disease, hemiballismus, senile chorea, convulsions, tardive dyskinesia, and Tourette's Syndromes, see eg Jankovic et al., Am. J. Psychiatry. (1999) Aug;156(8):1279-81 and Jankovic et al., Neurology (1997) Feb;48(2):358-62. [0003] The main pharmacological effect of tetrabenazine is to reduce the supply of monoamines (such as dopamine, serotonin and norepinephrine) in the central nervous system by inhibiting the human vacuolar monoamine transporter isoform 2 (hVMAT...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D455/06A61K31/473A61P25/14A61P25/24C07D471/04C07D491/14
CPCC07D455/06C07D471/04C07D491/14A61P25/00A61P25/14A61P25/24
Inventor I·克拉克R·特尔特尔G·约翰斯顿罗伯特·特莱德盖茨
Owner BIOVAIL LAB INT BARBADOS
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