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O-desmethylvenlafaxine and methods of preparing and using the same

Inactive Publication Date: 2005-09-08
WYETH LLC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0007] The compounds and compositions of the invention possess potent activity for treating or preventing the above-described disorders while reducing or avoiding adverse effects including, but not limited to, sustained hypertension, headache, asthenia, sweating, nausea, constipation, somnolence, dry mouth, dizziness, insomnia, nervousness, anxiety, blurred or blurry vision, and abnormal ejaculation / orgasm or impotence in males. In particular, adverse effects associated with the administration of racemic venlafaxine are reduced or avoided by the use of derivatives of venlafaxine. Compositions of the invention can also exhibit long half lives as compared to racemic venlafaxine.

Problems solved by technology

Studies directed at understanding the activity of O-desmethylvenlafaxine as compared to its parent have been hampered, however, by the metabolic difference between laboratory animals and man in their exposure to venlafaxine.
Despite the benefits of venlafaxine, it has adverse effects including, but not limited to, sustained hypertension, headache, asthenia, sweating, nausea, constipation, somnolence, dry mouth, dizziness, insomnia, nervousness, anxiety, blurred or blurry vision, and abnormal ejaculation / orgasm or impotence in males.
These adverse effects can significantly limit the dose level, frequency, and duration of drug therapy.

Method used

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  • O-desmethylvenlafaxine and methods of preparing and using the same

Examples

Experimental program
Comparison scheme
Effect test

example 1

5.1. Example 1

Synthesis of Venlafaxine

1-[cyano-(4-methoxyphenylmethyl]cyclohexanol

[0076] A solution of 4-methoxybenzylnitrile (53.5 g, 0.36 mol) in 400 mL THF was cooled to −78° C. followed by slow addition of a 2.0 M THF solution of lithium diisopropylamide (200 mL, 0.40 mol) maintaining the reaction temperature below −65° C. The reaction was stirred at −78° C. for 30 minutes. Cyclohexanone (39.5 g, 0.40 mol) was added at a rate such that the reaction temperature did not rise above −65° C. After the addition reaction was stirred at −78° C. for 2 hours, then was poured into 1 L saturated aqueous NH4Cl containing ice. The mixture was stirred for 15 minutes and was extracted with ethyl acetate (4×200 mL). Combined ethyl acetate layer was washed with water (3×100 mL), brine (1×100 mL) and dried (Na2SO4). Ethyl acetate was evaporated in vacuo to give colorless solid that was trichurated with hexane. The precipitate was filtered, washed with hexane, dried in vacuo to give colorless sol...

example 2

5.2. Example 2

Synthesis of (±)-O-desmethylvenlafaxine

[0080] A solution of diphenylphosphine (3.0 g, 16.1 mmol) in 20 mL THF was cooled to −10° C. followed by slow addition of a 1.6 M THF solution of n-BuLi (12.7 mL, 20.2 mmol) at a rate such that reaction temperature did not rise above 0° C. The reaction was stirred at 0° C. for 30 minutes. A solution of (±)-venlafaxine (1.0 g, 3.6 mmol) in 10 mL THF was added slowly at 0° C. The reaction was stirred at 0° C. for 15 minutes and allowed to warm to room temperature and stirred for 1 hour. It was then refluxed overnight. The reaction was cooled to room temperature and was poured slowly into 30 mL cold 3N HCl maintaining the temperature below 15° C. After stirring for 10 minutes, the aqueous layer was extracted with ethyl acetate (3×30 mL). The aqueous layer was adjusted to pH 6.8-6.9 by slow addition of solid NaHCO3. It was then saturated by adding NaCl and was extracted with ethyl acetate (6×30 mL). Combined ethyl acetate layer was d...

example 3

5.3. Example 3

Synthesis of (+)-N-desmethylvenlafaxine

[0081] To a solution of 1-[amino(4-methoxyphenyl)ethyl]cyclohexanol (1.0 g, 4.0 mmol) in 8 mL of toluene, 96% formic acid (0.37 g, 8.0 mmol) was added and the reaction was refluxed for 4 hours. It was cooled to room temperature and poured into 40 mL saturated aqueous NaHCO3. Toluene layer was separated and aqueous layer was extracted with toluene (3×15 mL). Combined toluene layer was washed with water (3×15 mL), brine (1×15 mL) and dried (Na2SO4). Toluene was evaporated in vacuo to give crude N-formyl compound as yellow gum (0.930 g, 83.8% yield). 1H (CDCl3): 7.95 (s, 1H), 7.15 and 6.85 (q, 4H), 5.80 (s, 1H), 4.10 (m, 1H), 3.80 (s, 3H), 3.50 (s, 1H), 2.80 (dd, 1H), 1.50 (m, 10H); 13C (CDCl3): 161.4, 158.8, 131.0, 130.7, 113.9, 73.0, 55.3, 54.2, 38.1, 36.1, 35.6, 25.6, 21.9, 21.8. (Impurity: 164.5, 129.0, 128.0, 125.0, 56.5, 42.0, 36.5, 35.5). MS (277, M+).

[0082] To a solution of crude N-formyl compound (0.585 g, 2.1 mmol) in 6 m...

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Abstract

Methods of preparing, and compositions comprising, derivatives of venlafaxine are disclosed. Also disclosed are methods of treating and preventing diseases and disorders including, but not limited to, affective disorders such as depression, bipolar and manic disorders, attention deficit disorder, attention deficit disorder with hyperactivity, Parkinson's disease, epilepsy, cerebral function disorders, obesity and weight gain, incontinence, dementia and related disorders.

Description

1. FIELD OF INVENTION [0001] The invention relates to derivatives of racemic venlafaxine, methods of their synthesis, compositions comprising them, and methods of their use. 2. BACKGROUND OF THE INVENTION [0002] A number of nontricyclic antidepressants have recently been developed that diminish the cardiovascular and anticholinergic liability characteristic of tricyclic antidepressants. Some of these compounds are used as anti-obesity agents and have shown promise in the treatment of cerebral function disorders such as Parkinson's disease and senile dementia. See, e.g., WO 94 / 00047 and WO 94 / 00114. The nontricyclic compound venlafaxine, chemically named (±)-1-[2-(dimethylamino)-1-(4-methoxyphenyl)ethyl]-cyclohexanol, is an antidepressant which has been studied extensively and which is described in, for example, U.S. Pat. No. 4,761,501 and Pento, J. T. Drugs of the Future 13(9):839-840 (1988). Its hydrochloride salt is currently commercially available in the United States under the t...

Claims

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Application Information

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IPC IPC(8): A61K9/48A61K9/20A61K31/135A61K31/137A61K47/12A61K47/26A61K47/38A61P3/04A61P15/10A61P23/00A61P25/00A61P25/04A61P25/06A61P25/08A61P25/14A61P25/16A61P25/20A61P25/22A61P25/24A61P25/28A61P25/30A61P43/00C07C209/50C07C215/46C07C215/64C07C217/14C07C217/74C07C231/02C07C233/18C07C235/34C07C255/36C07C255/37C07D295/192
CPCA61K9/2054A61K9/2059A61K9/4866A61K31/135C07C215/64C07D295/192C07C233/18C07C255/36C07C255/37C07C2101/14C07C217/74C07C2601/14A61P13/00A61P15/10A61P23/00A61P25/00A61P25/04A61P25/06A61P25/08A61P25/14A61P25/16A61P25/20A61P25/22A61P25/24A61P25/28A61P25/30A61P3/04A61P43/00A61P9/10
Inventor JERUSSI, THOMAS P.SENANAYAKE, CHRISANTHA H.
Owner WYETH LLC
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