Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-07-13
2002-10-15
Chang, Ceila (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C546S240000, C546S241000
Reexamination Certificate
active
06465490
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to a novel compound, its method of making, its method of use and intermediates thereof. It is a pharmaceutically active compound useful as an antagonist of serotonin at the 5HT
2A
receptor. It is useful in treating conditions and diseases such as schizophrenia, anxiety, variant angina, anorexia nervosa, Raynaud's phenomenon, intermittent claudication, coronary or peripheral vasospasms, fibromyalgia, cardiac arrhythmias, thrombotic illness, controlling the extrapyramidal symptoms associated with neuroleptic therapy, depressive and bipolar disorders, obsessive-compulsive disorders, insomnia and sleep apnea.
BACKGROUND OF THE INVENTION
(+)-&agr;-(2.3-Dimethoxyphenyl)-1-[2-(4-fluorophenyl)ethyl]-4-piperidinemethanol has the following structure:
It is a novel pharmaceutically active compound in the treatment of conditions and diseases useful as an antagonist of serotonin at the 5HT
2A
receptor, and as such, is useful in a variety of treatments such as schizophrenia, anxiety, variant angina, anorexia nervosa, Raynaud's phenomenon, intermittent claudication, coronary or peripheral vasospasms, fibromyalgia, cardiac arrhythmias, thrombotic illness, controlling the extrapyramidal symptoms associated with neuroleptic therapy, depression. bipolar disorders obsessive-compulsive disorders, insomnia and sleep apnea. &agr;-(2,3-Dimethoxyphenyl)-1-[2-(4-fluorophenyl)ethyl]-4-piperidinemethanol has been generically described in U.S. Pat. No. 5,169,096, issued Dec. 8, 1992, the disclosure of which is incorporated herein by reference. (+)-&agr;-(2,3-Dimethoxyphenyl)-1-[2-(4-fluorophenyl)ethyl]-4-piperidinemethanol was thereafter described in U.S. Pat. No. 5,134,149, issued Jul. 28, 1992, the disclosure of which is incorporated herein by reference. U.S. Pat. No. 5,700,813, issued Dec. 23, 1997, U.S. Pat. No. 5,700,812, issued Dec. 23, 1997, U.S. Pat. No. 5,561,144, issued Oct. 1, 1996, U.S. Pat. No. 5,721,249 issued Feb. 23, 1998 and U.S. Pat. No. 5,874,445 issued Feb. 23, 1999, the disclosure of each which is incorporated herein by reference, describe the use of (+)-&agr;-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenyl)ethyl]-4-piperidinemethanol as 5TH
2A
receptor antagonists in the treatment of a number of disease states as described above. Other U.S. Patents, which describe the use of the generic species in the treatment of a number of disease states, are U.S. Pat. Nos. 4,783,471; 4,877,798; 4,908,369; 4,912,117; 5,021,428; 5,106,855; 5,618,824 and U.S. Pat. No. 5,478,846, which generically discloses intermediates. Each of the preceding disclosures is incorporated herein by reference.
The compound of the present invention has been found to be an active metabolite of (+)-&agr;-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenyl)ethyl]-4-piperidinemethanol by virtue of its ability to act as an antagonist at the 5TH
2A
receptor and represents the major metabolite of (+)-&agr;-(2,3-dimethoxyphenyl)1-[2-(4-fluorophenyl)ethyl]-4-piperidinemethanol found in plasma. The unsulfated version of the present invention (+)-&agr;-(3-hydroxy-2-methoxyphenyl)-1-(2-(4-fluorophenyl)ethyl)-4-piperidinemethanol is also a metabolite of (+)-&agr;-(2,3-dimethoxyphenyl)1-[2-(4-fluorophenyl)ethyl]-4-piperidinemethanol as described in Heath, T. G. et al.
J. Am. Soc. Mass Spectrom.
(1997), 8(4), 371-379, and Scott, D. et al.
J. Pharm. Biomed. Anal.
(1998), 17(1), 17, incorporated herein by reference. Even though the present invention is a mono sulfated conjugate of (+)-&agr;-(3-hydroxy-2-methoxyphenyl)-1-(2-(4-fluorophenyl)ethyl)-4-piperidinemethanol, unexpectedly, according to tests described hereafter, it has been found to cross the blood-brain barrier and therefore may be useful in the treatment of central nervous system conditions or diseases which are treated by antagonizing the effects of serotonin at the 5TH
2A
receptor.
It is an object of the present invention to provide a compound useful in treating a variety of diseases or conditions. This compound should have a binding profile (affinity or lack of affinity for specific receptors), which permits therapeutic activity without undue side effects. For example, too much affinity for the alphal receptor may result in orthostatic hypotension and sedation. Too much affinity for the dopamine 2 (D
2
) receptor can result in hyperprolactinemia, extrapyramidal side effects (EPS) and tardive dyskinesia. Also, preferably the present invention should cross the blood-brain barrier in order to be active against diseases or conditions that affect the central nervous system. The present invention solves these problems by having an effective binding profile sufficient to treat certain diseases or conditions without significant side effects and treats certain central nervous systems diseases or conditions.
SUMMARY OF THE PRESENT INVENTION
The present invention is a compound of Formula I, II or III
or a pharmaceutically acceptable salt thereof, and methods for the preparation of said compounds.
The present invention also comprises a pharmaceutical composition comprising the compounds of formula I, II or III and a pharmaceutically acceptable carrier; a method of treating a patient for diseases of schizophrenia, anxiety, variant angina, anorexia nervosa, Raynaud's phenomenon, intermittent claudication, coronary or peripheral vasospasms, fibromyalgia, cardiac arrhythmias, thrombotic illness and in controlling the extrapyramidal symptoms associated with neuroleptic therapy, depressive and bipolar disorders, obsessive-compulsive disorders, insomnia and sleep apnea, by administering a compound of formula I, II or III. Further, the present invention also comprises an intermediate, and methods of making the unsulfated versions of the forgoing compounds. The present invention also comprises collecting (isolating) the compounds of interest from a sample collected from a patient.
DETAILED DESCRIPTION OF THE PRESENT INVENTION
(1) “Pharmaceutically acceptable salt” means either an acid addition salt or a basic addition salt, which is compatible with treatment of patients for the intended use.
“Pharmaceutically acceptable acid addition salt” is a non-toxic organic acid addition salt of the base compounds represented by Formula I, II or III or any of its intermediates. Some examples of inorganic acids which form suitable salts include hydrochloric, hydrobroinic, sulfixic 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 tricarboxylic acids. Examples of such acids are acetic, glycolic, lactic, pyruvic, malonic, succinic, glutaric, fumaric, malic, tartaric, citric, ascorbic, maleic, hydroxymaleic, benzoic, hydroxybenzoic, phenylacetic, cinnamic, salicylic, 2-phenoxybenzoic, and sulfonic acids such as methane sulfonic acid, p-toluenesulfonic acid, and 2-hydroxyethane sulfonic acid. Such salts can exist in either a hydrated or substantially anhydrous form. In general, the acid addition hydrophilic organic salts in comparison to their free base forms generally demonstrate higher melting points.
“Pharmaceutically acceptable base addition salts” means non-toxic organic or inorganic basic addition salts of the compounds of Formula (I) or any of its intermediates. Examples are alkali metal or alkaline-earth metal hydroxides such as sodium, potassium, calcium or organic amines such as methylamine, trimethylamine and picoline.
(2) “Patient” means a warm blooded animal, such as, for example, rat, mouse, dog, cat, guinea pig, and primates such as a human.
(3) “Treat” or “treatment” means to prevent or alleviate symptoms, eliminate the causation of the symptoms either on a temporary basis, or to prevent or slow the appearance of symptoms of the named disorder or condition.
(4) “Therapeutically sufficient amount” means a quantity of the compound that is effective in treating the named disorder
Bernotas Ronald Charles
Brown Paul Wayne
Emmons Gary Thomas
King Chi-Hsin Richard
Aventis Pharmaceuticals Inc.
Chang Ceila
Gupta Balaram
Strupczewski Joseph T.
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