Doxepin trans isomers and isomeric mixtures and methods of using the same to treat sleep disorders

a technology of doxepin and isomeric mixtures, which is applied in the direction of biocide, drug compositions, nervous disorders, etc., can solve the problems of many physicians being reluctant to prescribe benzodiazepines, withdrawal symptoms such as agitation, rebound insomnia, confusion,

Inactive Publication Date: 2010-07-15
SOMAXON PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0031]In some embodiments, the present invention relates to a composition including doxepin, a metabolite of doxepin, a salt of doxepin, a salt of a metabolite of doxepin, a prodrug of doxepin, or a prodrug of a metabolite of doxepin, wherein the ratio of the trans/cis-isomers is more than that found in the doxepin as typically prepared.
[0032]In some embodiments, the present invention relates to a method for the treatment of a patient suffering from insomnia including providing a composition enriched in trans isomer compared to ratio o...

Problems solved by technology

While these agents have proven to be efficacious and relatively safe, benzodiazepines are associated with a multitude of adverse effects, including residual daytime sedation (“hangover”), amnesia, memory loss and respiratory depression.
Tolerance to the hypnotic effects of the benzodiazepines is common and abrupt discontinuation can result in withdrawal symptoms such as agitation, rebound insomnia, perceptual changes, confusion, disorientation and even seizures.
A...

Method used

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  • Doxepin trans isomers and isomeric mixtures and methods of using the same to treat sleep disorders
  • Doxepin trans isomers and isomeric mixtures and methods of using the same to treat sleep disorders
  • Doxepin trans isomers and isomeric mixtures and methods of using the same to treat sleep disorders

Examples

Experimental program
Comparison scheme
Effect test

example 1

[0111]Doxepin is prepared by the following method.

[0112](a) A Grignard compound is prepared in the conventional manner from 4.8 g (0.2 gram-atom) magnesium in 100 ml ether and 30 g (34 ml) (3-chloropropyl)-tertbutyl-ether and 16.40 grams (0.078 mol) 6,11-dihydrodibenzo-[b,e]-oxepine-11-one dissolved in 100 ml ether is added in dropwise fashion so that the contents of the flask boil lightly. The mixture is heated for 1 hour with agitation in a reflux condenser to complete the reaction and then it is decomposed with ammonium chloride solution. The product which is obtained by separating, drying and eliminating the solvent produced, when the ether residue (24.0 g) is extracted with ligroin, amounts to 20.3 g (80.0% of theory) of 11-(3-tertbutoxypropyl)-11-hydroxy-6,11-dihydrodibenzo-[b,e]-oxepine, having a melting point of 124-126° C. The (3-chloropropyl)-tertbutyl ether is thereafter obtained in the following manner: 19 g (0.2 mol) 1-chloropropanol-(3), 50 ml liquid isobutylene and 0....

example 2

Preparation of Doxepin Isomer

[0116]Five grams of the cis / trans mixture of doxepin hydrochloride is converted to the free base and then to the maleate salt, M.P. 168-169° C. Several recrystallizations from ethanol afford a pure isomeric maleate, M.P. 172-173° C. This is reconverted to the free base and then to the hydrochloric acid-addition salt. This is purified by recyrstallization from a mixture of ethanol and ether; M.P. 192-193° C. The other pure isomer is isolated by the concentration of the crystallization liquors to dryness, followed by converting the residue to the free base and then converting the base to the hydrochloric-acid addition salt. After re-crystallization from a mixture of ethanol and ether, the salt has a M.P. of 209-210.5° C.

example 3

Preparation of Desmethyldoxepin

[0117]Desmethyldoxepin is prepared according to the following method. Anhydrous 3-methylaminopropyltriphenylphosphonium bromide hydrobromide (1530 g) prepared as in U.S. Pat. No. 3,509,175, is suspended in 4.5 l dry tetrahydrofuran and 6.0 moles of butyl lithium in heptane is added during 1 hour. After an additional 30 minutes, 483 g of 6,11-dihydrodibenz(b,e)oxepin-11-one, is added to the deep red solution and the reaction is maintained at reflux for 10 hours. Water, 500 ml, is added at room temperature and the solvent is removed in vacuo. The crude residue is treated with 10% hydrochloric acid until acidic (pH 2) and then 1.5 l benzene is added. After stirring, the mixture separates into three phases (an insoluble hydrochloride salt product phase, an aqueous phase and an organic phase). The benzene layer is removed by decantation and the remaining mixture is rendered basic with 10% sodium hydroxide solution and is extracted with 3×1500 ml portions of...

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Abstract

The invention relates to use of the trans-(E) isomer or isomeric mixtures containing specified ratios of the trans-(E) and cis-(Z) isomers of doxepin, metabolites of doxepin, pharmaceutically-acceptable salts of doxepin and prodrugs of the same; compositions containing the same, for the treatment of sleep disorders

Description

RELATED APPLICATIONS[0001]This application is a continuation-in-part of U.S. application Ser. No. 12 / 022,788, filed Jan. 30, 2008, which claims the benefit of, and priority to, U.S. Provisional Application No. 60 / 898,378, filed Jan. 30, 2007; and U.S. application Ser. No. 12 / 022,788 is a continuation-in-part of U.S. application Ser. No. 11 / 804,720, filed May 18, 2007, which claims priority to U.S. Provisional Application Nos. 60 / 801,824, filed May 19, 2006, and 60 / 833,319, filed Jul. 25, 2006.BACKGROUND OF THE INVENTION[0002]1. Field of the Invention[0003]The invention relates to use of the trans-(E) isomer or isomeric mixtures containing specified ratios of the trans-(E) and cis-(Z) isomers of doxepin and metabolites of doxepin, as well as pharmaceutically-acceptable salts and prodrugs of the same; and compositions containing the same, for the treatment of sleep disorders.[0004]2. Description of the Related Art[0005]Sleep is essential for health and quality of life. Insomnia is a s...

Claims

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Application Information

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IPC IPC(8): A61K31/335A61P25/20
CPCA61K31/335A61P25/20
Inventor DUBE, SUSAN E.KAVEY, NEIL B.
Owner SOMAXON PHARMA
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