Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-02-22
2002-03-05
Weddington, Kevin E. (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S393000, C514S394000, C514S653000
Reexamination Certificate
active
06353005
ABSTRACT:
The invention relates to methods and compositions for the prevention, treatment, or management of gastrointestinal disorders or symptoms thereof, by administering one or more agent(s) or compound(s) that simultaneously or sequentially act on a 5-HT
3
receptor, a 5-HT
4
receptor, and either an H
2
receptor or a proton pump.
2. Background of the Invention
Gastrointestinal disorders are common disorders that affect the gastrointestinal tract, i.e., the stomach and intestines. Various gastrointestinal disorders exist, including: gastro-esophageal reflux disease, emesis, gastrointestinal motility dysfunction, gastrointestinal ulcers, pathological hypersecretory conditions, and gastric hyperacidity. These diseases may be treated by various non-invasive means, such as administering to a patient a therapeutic agent, such as ZANTAC® (ranitidine), TRITEC® (ranitidine), AXID® (nizatidine), TAGAMET® (cimetidine), PREVACID® (lansoprazole), PEPCID®, PEPCID AC® ACID CONTROLLER™, MYLANTA AR ACID REDUCER™ (famotidine), PRILOSEC® (omeprazole), and others. New pharmaceutical compounds and preparations are continually being developed.
U.S. Pat. Nos. 4,962,115, 5,057,525, and 5,137,896 (collectively “Van Daele”) disclose N-(3-hydroxy-4-piperidenyl)benzamides. These compounds are said to stimulate the motility of the gastrointestinal system. Van Deale states that the cis and trans diastereomeric racemates of these compounds may be obtained separately by conventional methods, and the cis and trans diastereomeric racemates may be further resolved into their optical isomers. One such racemate, Cisapride, is chemically named cis4-amino-5-chloro-N-[1-[3-(4-fluorophenoxy)propyl]-3-methoxy-4-piperidinyl]-2-methoxybenzamide. Schapira et al.,
Acta Gastroenterolog. Belg., LIII:
446-457 (1990). Cisapride is used primarily to treat gastroesophageal reflux disease (“GERD”), which is characterized as the backward flow of the stomach contents into the esophagus. Cisapride is commercially available as the racemic mixture of the cis(−) and cis(+) diastereomeric enantiomers of cisapride known as PROPULSID®.
Benzamide derivatives have several prominent pharmacological actions due to their effects on neuronal systems modulated by the neurotransmitter serotonin. It has been reported that a major site of production and storage of serotonin is the enterochromaffin cell of the gastrointestinal mucosa. It was also reported that serotonin provides a powerful intestinal transit and decreasing absorption time, as occurs with diarrhea. This stimulating action is also associated with nausea and vomiting.
Because of their modulation of the serotonin neuronal system in the gastrointestinal tract, some benzamide derivatives are effective antiemetic agents and are used to control vomiting during cancer chemotherapy or radiotherapy. Costall et al.,
Neuropharmacology,
26:1321-1326 (1987). This action is the result of an ability to block serotonin at specific sites, particularly Type-3 5-hydroxytryptamine (5-HT
3
) receptors. Clarke et al.,
Trends in Pharmacological Sciences,
10:385-386 (1989). Chemotherapy and radiation therapy can induce nausea and vomiting by damaging enterochromaffin cells in the gastrointestinal tract. As a result, the neurotransmitter serotonin is released and 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. Barnes et al.,
J. Pharm. Pharmacol.,
40:586-588 (1988).
A second prominent action of certain benzamide derivatives is in augmenting gastrointestinal smooth muscle activity from the esophagus to the proximal small bowel, thus accelerating esophageal and small intestinal transit, as well as facilitating gastric emptying and increasing lower esophageal sphincter tone. Decktor et al.,
Eur. J. Pharmacol.,
147: 313-316 (1988). Although the benzamide derivatives are not cholinergic receptor agonists per se, the aforementioned smooth muscle effects may be blocked by muscarinic receptor blocking agents such as atropine or inhibitors of neuronal transmissions, such as the tetrodotoxin type that block sodium channels. Fernandez and Massingham,
Life Sci.,
36: 1-14 (1985). Similar blocking activity has been reported for the contractile effects of serotonin in the small intestine. Craig and Clarke,
Brit. J. Pharmacol.,
96: 247P (1989). It is believed that the primary smooth muscle effects of some benzamide derivatives are the result of an agonist action upon a class of serotonin receptors referred to as 5-HT
4
receptors, which are located on interneurons in the myenteric plexus of the gut wall. Clarke et al.,
Trends in Pharmacological Sciences,
10: 385-386 (1989) and Dumuis et al.,
N. S. Arch. Pharmacol.,
340: 403-410 (1989). Activation of these receptors subsequently enhances the release of acetylcholine from parasympathetic nerve terminals located near surrounding smooth muscle fibers. It is the combination of acetylcholine with its receptors on smooth muscle membranes which is the actual trigger for muscle contraction.
It has been reported that cisapride enters the central nervous system and binds to 5-HT
4
receptors. This indicates that cisapride may have centrally-mediated effects. Cisapride is a potent ligand at 5-HT
4
receptors, which are located in several areas of the central nervous system. Dumuis et al.,
N. S. Arch. Pharmacol.,
340: 403-410 (1989). Modulation of serotonergic systems may have a variety of behavioral effects.
The co-administration of racemic cisapride with other therapeutic agents causes inhibitory problems with the metabolism of cisapride by the liver. For example, ketoconazole has a pronounced effect on cisapride kinetics resulting from the inhibition of the metabolic elimination of cisapride and leads to an 8-fold increase of the steady-state plasma levels.
Physician's Desk Reference®,
Medical Economics Co., Inc., p. 1308-1309, 52
nd
Edition (1998). Interaction of racemic cisapride and other therapeutic agents can also potentiate cardiovascular side effects, such as cardiotoxicity. This potentiation occurs when other drugs present in the patient's system interfere with the metabolism of cisapride, thereby causing a build up of racemic cisapride in the body.
These interactions are a significant drawback to the use of racemic cisapride; in particular, because racemic cisapride is often used before, with, or immediately after another therapeutic agent. In addition, administration of racemic cisapride to a human has been found to cause adverse effects such as cardiac arrhythmia, including ventricular tachycardia, ventricular fibrillation, Q
T
prolongation, and torsades de pointes, central nervous system (“CNS”) effects, increased systolic pressure, interactions with other drugs, diarrhea, abdominal cramping, and cardiac depression.
Racemic cisapride in humans is metabolized mainly by oxidative N-dealkylation of the piperidine nitrogen or by aromatic hydroxylation occurring on either the 4-fluorophenoxy or benzamide rings. Meuldermans et al.,
Drug Metab. Dispos.,
16(3):410-419 (1988); and Meuldermans et al.,
Drug Metab. Dispos.,
16(3):403-409 (1988). Norcisapride, chemically named 4-amino-5-chloro-N-(3-methoxy-4-piperidinyl)-2-methoxybenzamide, is an active metabolite of cisapride.
Recently, investigators have reported that the optically pure (+) stereoisomer of the cisapride metabolite norcisapride exhibits many useful characteristics, but without certain side effects of racemic cisapride. Specifically, U.S. Pat. No. 5,739,151 discloses a method of eliciting an antiemetic effect and treating other conditions using optically pure (+) norcisapride.
Other agents or compounds which have been studied for the treatment of gastrointestinal diseases include proton pump inhibitors and H
2
receptor antagonists. Proton pump inhibi
Barberich Timothy J.
Rubin Paul D.
Sepracor Inc.
Weddington Kevin E.
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