Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-10-30
2002-04-30
Henley, III, Raymond (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
Reexamination Certificate
active
06380216
ABSTRACT:
The present invention is directed to the use of compound (+)-&agr;-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenyl)ethyl]-4-piperidinemethanol or its pharmaceutically acceptable acid addition salts in a method of treating Depressive Disorders and Bipolar Disorders in patients in need of such therapy.
BACKGROUND OF THE INVENTION
The compound (+)-isomer of &agr;-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenyl)ethyl]-4-piperidinemethanol is generically described by U.S. Pat. No. 5,169,096 and specifically described in U.S. Pat. No. 5,134,149, both of which are hereby incorporated by reference. This compound is described therein as a 5HT
2A
receptor antagonist. It has since been discovered that this compound is useful in the treatment of Depressive Disorders and Bipolar Disorders.
The compound of the present invention solves the complicated problem of treating patients for Depression Disorders of Bipolar Disorders through an unusual compound profile. It is a highly selective 5HT
2A
receptor antagonist having subnanomolar affinity for the 5HT
2A
receptor versus affinities of greater than 100 nM for the 5HT
2C
, D
1
(dopamine), D
2
(dopamine), and &agr;-1 receptors in in vitro models.
It has a lower affinity for receptors often associated with unwanted side effects, e.g., lower affinity for the D
2
receptor suggests less potential to cause extrapyramidal side effects, little affinity for the cholinergic M1/M2 receptors suggests less cholinergic side effects such as dry mouth, delirium and cognitive impairment. It is orally active, non-toxic at therapeutic doses and potent. It is also capable of being sealed-up for commercial synthesis. Additionally, neurochemical studies indicate that there is a serotonin/dopamine interaction following chronic administration of this compound as described in
Life Sciences
56(25): 2209-2222 (1995), incorporated herein by reference. The combination of the foregoing characteristics produces a unique compound for treating patients having either Depressive Disorders of Bipolar Disorders.
SUMMARY OF THE INVENTION
In accordance with the present invention, a compound has been discovered which is useful in the treatment of Depressive Disorders and Bipolar Disorders, the (+)-isomer of &agr;-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenyl)ethyl]-4-piperidinemethanol or the pharmaceutically acceptable salts thereof. It is described by the following formula:
A therapeutically effective amount of this compound or its pharmaceutically acceptable acid addition salt is administered to a patient in need of such therapy to treat Depressive Disorders or Bipolar Disorders.
DETAILED DESCRIPTION OF THE INVENTION
As used in this application:
a) the expression “pharmaceutically acceptable acid addition salts” is intended to apply to any non-toxic organic or inorganic acid addition salt of the compound of the present invention. Illustrative inorganic acids which form suitable salts include hydrochloric, hydrobromic, sulfuric and phosphoric acid and acid metal salts such as sodium monohydrogen orthophosphate and potassium hydrogen sulfate. Illustrative organic acids which form suitable salts include the mono-, di- and tri-carboxylic acids. Illustrative of such acids are, for example, acetic, glycolic, lactic, pyruvic, malonic, succinic, glutaric, fumaric, malic, tartaric, citric, ascorbic, maleic, hydroxymaleic, benzoic, hydroxybenzoic, phenylacetic, cinnamic, salicyclic, 2-phenoxybenzoic, p-toluenesulfonic acid and sulfonic acids such as methanesulfonic acid and 2-hydroxyethanesulfonic acid. Either the mono- or di-acid salts can be formed, and such salts can exist in either a hydrated or substantially anhydrous form. In general, the acid addition salts of these compounds are soluble in water and various hydrophilic organic solvents and which in comparison to their free base forms, generally demonstrate higher melting points.
b) any reference to (+)-&agr;-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenyl)ethyl]-4-piperidinemethanol should be construed as encompassing the free basis of this compound or an acid addition salt of this compound.
c) the term “patient” refers to a warm-blooded animal, such as for example rats, mice, dogs, cats, guinea pigs, and primates such as humans, and;
d) the term “treat” refers to either relieving or alleviating the patient's disease or condition.
The (+)-isomer of &agr;-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenyl)ethyl]-4-piperidinemethanol can be prepared by methods known in the art as was discussed in European Application 0 208 235 (U.S. Pat. No. 5,169,096). One suitable method is disclosed below in Reaction Scheme I:
In Step A of Reaction Scheme I, an esterification reaction is carried out between racemic &agr;-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenyl)ethyl]-4-piperidinemethanol (structure 1) and the (+)-isomer of &agr;-methoxyphenylacetic acid (structure 2). This esterification produces the diastereomeric mixture identified as structure 3. These diastereomers are subjected to silica gel chromatography which separates the two diastereomers, thereby isolating the (+,+) diastereomer as is depicted in Step B. In Step C, the (+,+) diastereomer is hydrolysed which produces the (+)-isomer of &agr;-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenyl)ethyl]-4-piperidinemethanol.
The esterification reaction can be carried out using techniques known in the art. Typically approximately equivalent amounts of racemic &agr;-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenyl)ethyl]-4-piperidinemethanol and the (+)-isomer of &agr;-methoxyphenylacetic acid are contacted in an organic solvent such as methylene chloride, THF, chloroform toluene and heated to reflux for a period of time ranging from 5 to 24 hours. The esterification is typically carried out in the presence of an equivalent amount of dicyclohexylcarbodiimide and a catalytic amount of 4-dimethylaminopyridine. The resulting diastereomers can be isolated by filtration of the dicyclohexylurea and evaporation of the filtrate.
The diastereomers are then subjected to silica gel chromatography which separates the (+,+) and the (−,+) diastereomers. This chromatagraphic separation may be carried out as is known in the art. A 1:1 mixture of hexane and ethyl acetate is one suitable eluent.
The resulting (+,+) diastereomer is then subjected to a hydrolysis reaction which produces the (+)-isomer of &agr;-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenyl)ethyl]-4-piperidinemethanol. The hydrolysis is carried out by contacting the diastereomer with an excess of a base such as potassium carbonate in an aqueous alcoholic solution. The hydrolysis is carried out at a temperature of about 15 to 30° C. for a period of time ranging from 2 to 24 hours. The resulting (+)-isomer of &agr;-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenyl)ethyl]-4-piperidinemethanol may then be recovered by dilution with water and extraction with methylene chloride. It is then purified by recrystallization from a solvent system such as cyclohexane/hexane or ethyl acetate/hexane.
Methods for producing the starting materials of Reaction Scheme I are known in the art. For example, U.S. Pat. No. 4,783,471 teaches how to prepare racemic &agr;-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenyl)ethyl]-4-piperidinemethanol. This patent is hereby incorporated by reference. Examples No. 1 and 2 of this application also teach suitable methods. Alternatively, racemic &agr;-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenyl)ethyl]-4-piperidinemethanol can be prepared in the following manner. Initially 4-hydroxypiperidine is subjected to an N-alkylation reaction with p-fluorophenylethyl bromide which produces 4-hydroxy-1-[2-(4-fluorophenyl)ethyl]-piperidine. This compound is brominated with Ph
3
P.Br
2
which produces 4-bromo-1-[2-(4-fluorophenyl)ethyl]piperidine. This compound is contacted with Mg thereby forming a Grignard Reagent which is then reacted with 2,3-dim
Aventis Pharmaceuticals Inc.
Gupta Balaram
Henley III Raymond
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