Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-10-23
2001-11-06
Jarvis, William R. A. (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
06313144
ABSTRACT:
1. TECHNICAL FIELD
This invention relates to novel compositions of matter containing optically pure (−) norcisapride. These compositions possess potent activity in treating gastro-esophageal reflux disease while substantially reducing adverse effects associated with the administration of racemic cisapride including but not limited to diarrhea, abdominal cramping, cardiac depression, and elevations of blood pressure and heart rate. Additionally, these novel compositions of matter containing optically pure (−) norcisapride are useful in treating emesis and such other conditions as may be related to the activity of (−) norcisapride as a prokinetic agent, including but not limited to dyspepsia, gastroparesis, constipation, and intestinal pseudo-obstruction, while substantially reducing adverse effects associated with the administration of racemic cisapride. Also disclosed are methods for treating the above-described conditions in a human while substantially reducing adverse effects that are associated with cisapride, by administering the (−) isomer of norcisapride to a human in need of such treatment. Further disclosed are methods of treating various disease states in humans by co-administering optically pure (−) norcisapride and another therapeutic agent, while unexpectedly avoiding the adverse effects associated with administering cisapride and a therapeutic agent.
The active compound of these compositions and methods is an optically pure isomer of a metabolic derivative of cisapride, which is described in Meuldermans, W. et al.,
Drug Metab. Dispos.
16(3): 410-419, 1988 and Meuldermans, W. et al.,
Drug Metab. Dispos.
16(3): 403-409, 1988.
Chemically, the active compound, of the presently disclosed compositions and methods, is the (−) isomer of the metabolic derivative of cis-4-amino-5-chloro-N-[
1-[3
-(4-fluorophenoxy) propyl]-3-methoxy-4-piperidinyl]-2-methoxybenzamide (hereinafter referred to as “cisapride”), known as 4-amino-5-chloro-N-(3-methoxy-4-piperidinyl)-2 methoxybenzamide hereinafter referred to as “(−) norcisapride.” The term “(−) isomer of norcisapride” and particularly the term “(−) norcisapride” encompass optically pure and substantially optically pure (−) norcisapride. Similarly, as used herein, the terms “racemic cisapride”, “racemic norcisapride” or “racemic mixture of cisapride” or “racemic mixture of norcisapride” refer to the cis diastereomeric racemates.
Cisapride is available commercially only as the 1:1 racemic mixture of the cis diastereomeric racemate known as “Prepulsid™.” Cisapride is available only as a mixture of optical isomers, called enantiomers, i.e., a mixture of cis(+) and cis(−) cisapride.
2. BACKGROUND OF THE INVENTION
2.1. Steric Relationship and Drug Action
Many organic compounds exist in optically active forms, i.e., they have the ability to rotate the plane of plane-polarized light. In describing an optically active compound, the prefixes D and L or R and S are used to denote the absolute configuration of the molecule about its chiral center(s). The prefixes d and l or (+) and (−) are employed to designate the sign of rotation of plane-polarized light by the compound, with (−) or l meaning that the compound is levorotatory. A compound prefixed with (+) or d is dextrorotatory. For a given chemical structure, these compounds, called stereoisomers, are identical except that they are mirror images of one another. A specific stereoisomer may also be referred to as an enantiomer, and a mixture of such isomers is often called an enantiomeric or racemic mixture.
Stereochemical purity is of importance in the field of pharmaceuticals, where 12 of the 20 most prescribed drugs exhibit chirality. A case in point is provided by the L-form of the beta-adrenergic blocking agent, propranolol, which is known to be 100 times more potent than the D-enantiomer.
2.2. Pharmacologic Action
U.S. Pat. Nos. 4,962,115, 5,057,525 and 5,137,896 (collectively “Van Daele”) disclose N-(3-hydroxy-4-piperidenyl)benzamides including the cis and trans diastereomeric racemates of cisapride. Van Daele discloses that these compounds, the pharmaceutically acceptable acid addition salts thereof and the stereochemically isomeric forms thereof, stimulate the motility of the gastrointestinal system. Van Daele states that the diastereomeric racemates of these compounds may be obtained separately by conventional methods and that these diastereomeric racemates may be further resolved into their optical isomers. Van Daele also reports the “lowest effective concentration . . . whereby a significant stimulation of the acetylcholine release is noted”, for cis(+) and cis(−) cisapride, to be 0.01 mg/L and 0.04 mg/L respectively, while the “lowest effective dose whereby antagonistic effects of dopamine-induced gastric relaxation are observed” is reported to be 0.63 mg/L for both cis(+) and cis(−) cisapride. Therefore, Van Daele teaches that cis(+) and cis(−) cisapride have roughly identical pharmacological profiles.
Cisapride is one of a class of compounds known as benzamide derivatives, the parent compound of which is metoclopramide (See: Schapira et al.,
Acta Gastroenterolog. Belg
. LIII: 446-457, 1990). As a class, these benzamide derivatives have several prominent pharmacological actions. The prominent pharmacological activities of the benzamide derivatives are due to their effects on the neuronal systems which are modulated by the neurotransmitter serotonin. The role of serotonin, and thus the pharmacology of the benzamide derivatives, has been broadly implicated in a variety of conditions for many years (See Phillis, J. W., “
The Pharmacology of Synapses”
, Pergamon Press, Monograph 43, 1970; Frazer, A. et al.,
Annual Rev. of Pharmacology and Therapeutics
30: 307-348, 1990). Thus, research has focused on locating the production and storage sites of serotonin as well as the location of serotonin receptors in the human body in order to determine the connection between these sites and various disease states or conditions.
In this regard, it was discovered that a major site of production and storage of serotonin is the enterochromaffin cell of the gastrointestinal mucosa. It was also discovered that serotonin has a powerful stimulating action on intestinal motility by stimulating intestinal smooth muscle, speeding intestinal transit, and decreasing absorption time, as in diarrhea. This stimulating action is also associated with nausea and vomiting.
Because of their modulation of the serotonin neuronal system in the gastrointestinal tract, many of the benzamide derivatives are effective antiemetic agents and are commonly used to control vomiting during cancer chemotherapy or radiotherapy, especially when highly emetogenic compounds such as cisplatin are used (See: Costall et al.,
Neuropharmacology
26: 1321-1326, 1987). This action is almost certainly the result of the ability of the compounds to block the actions of serotonin (5HT) at specific sites of action, called the 5HT3-receptor, which was classically designated in the scientific literature as the serotonin M-receptor (See: Clarke et al.,
Trends in Pharmacological Sciences
10: 385-386, 1989). Chemo- and radio-therapy may induce nausea and vomiting by the release of serotonin from damaged enterochromaffin cells in the gastrointestinal tract. Release of the neurotransmitter serotonin stimulates both afferent vagal nerve fibers (thus initiating the vomiting reflex) and serotonin receptors in the chemoreceptor trigger zone of the area postrema region of the brain. The anatomical site for this action of the benzamide derivatives, and whether such action is central (CNS), peripheral, or a combination thereof, remains unresolved (See: Barnes et al.,
J. Pharm. Pharmacol.
40: 586-588, 1988). Cisapride, like the other benzamide derivatives may be an effective antiemetic agent based on its ability to modulate the activity of serotonin at the 5HT3 receptor.
A second prominent action of the
Aberg A. K. Gunnar
McCullough John R.
Jarvis William R. A.
Pennie & Edmonds LLP
Sepracor Inc.
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