Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-04-05
2001-09-04
Spivack, Phyllis G. (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S183000, C514S230500, C514S254060, C514S284000, C514S304000, C514S305000, C514S306000, C514S394000, C514S397000
Reexamination Certificate
active
06284770
ABSTRACT:
This application is a rule 371 Application of PCT/EP98/06278, filed Oct. 5, 1998, which claims priority to Great Britain Patent Application No. 9721139.5, filed Oct. 7, 1997.
The invention relates to a new medical use for compounds which act as antagonists of 5-hydroxytryptamine (5-HT) at 5-HT
3
receptors.
5-HT
3
receptor antagonists may be identified by methods well known in the art, for example by their ability to inhibit 3-(5-methyl-1H-imidazole4-yl)-1-[1-[
3
H]-methyl-1H-indol-3-yl]-1-propanone binding in rat entorhinal cortex homogenates (following the general procedure described by G Kilpatrick et al, Nature, 1987, 330, 746-748), and/or by their effect on the 5-HT-induced Bezold-Jarisch (B-J) reflex in the cat (following the general method described by A Butler et al, Br. J. Pharmacol., 94, 397-412 (1988)).
A number of different 5-HT
3
receptor antagonists have been disclosed, for example those of group A: indisetron, Ro-93777, YM-114, granisetron, talipexole, azasetron, tropisetron, mirtazapine, ramosetron, ondansetron, lerisetron, alosetron, N-3389, zacopride, cilansetron, E-3620, lintopride, KAE-393, itasetron, mosapride and dolasetron.
In UK Patent No. 2209335, incorporated herein by reference, there is disclosed, inter alia, the compound 2,3,4,5-tetrahydro-5-methyl-2-[(5-methyl-1H-imidazol4-yl)methyl]-1H-pyrido[4,3-b]indol-1-one, now known as alosetron, which may be represented by the formula (I):
and pharmaceutically acceptable salts, solvates and pharmaceutically acceptable equivalents thereof, in particular its hydrochloride salt.
5-HT
3
receptor antagonists are known to be useful in the treatment of a variety of conditions involving 5-HT
3
receptor-mediated mechanisms, including in particular emesis.
Irritable bowel syndrome (IBS) is the most common diagnosis made by gastroenterologists (1) and is characterised by abdominal pain and discomfort and altered bowel functions (2-4). To date, no laboratory or structural defects have been identified in IBS and the formal diagnosis is based upon a constellation of symptoms defined by either the Manning (5) or Rome Criteria (6).
The current understanding of the pathophysiology or etiology of IBS is limited, and no proven effective therapy is available (3,7). Moreover, many patients gain slight or even no relief from such therapies. Thus, there is a real need to develop new medicines for the treatment of IBS.
Over the last two decades compelling evidence has accumulated that a state of enhanced perception of visceral stimuli develops in patients with IBS (2,3,8-10). In balloon distension studies of the colon or rectum the threshold for sensation of pain is lower in IBS patients compared to controls, and this has been proposed as a biological marker for IBS (11). In view of the evidence for enhanced visceral perception in IBS and the frequent occurrence of pain, any agent considered to be of utility in the treatment of IBS should demonstrate effectiveness in the relief of pain.
Of the classes of therapeutic agents which have been proposed for the treatment of abdominal pain in IBS, 5-HT
3
receptor antagonists are among the most promising. In animal models, these agents have been shown to decrease visceral pain responses (12,13). Furthermore, the 5-HT
3
receptor antagonist, ondansetron, has been shown to slow colonic transit in normal volunteers (14-15). In patients with IBS ondansetron increases rectal compliance (16) and in diarrhoea-predominant IBS patients ondansetron improves stool consistency (17-19). Ondansetron also inhibits the contractile response of the colon in healthy volunteers in the early postprandial period (20), the time when many IBS patients experience symptoms. A second 5-HT
3
receptor antagonist, granisetron, has also been shown to produce a decrease in rectal sensitivity, and reduce post-prandial motor activity in IBS patients (21).
Alosetron is a potent and selective 5-HT
3
receptor antagonist, and in preliminary reports, alosetron has been shown to improve abdominal pain (22), and to slow colonic transit in IBS patients (23).
Surprisingly, it has now been found that 5-HT
3
receptor antagonists represent a particularly effective and well tolerated therapy in nonconstipated female IBS patients.
According to one aspect the invention therefore provides a 5-HT
3
receptor antagonist or a pharmaceutically acceptable derivative thereof for use in the treatment of nonconstipated female IBS.
In one preferred aspect the invention provides a 5-HT
3
receptor antagonist or a pharmaceutically acceptable derivative thereof for use in the treatment of diarrhea predominant female IBS.
In another preferred aspect the invention provides a 5-HT
3
receptor antagonist or a pharmaceutically acceptable derivative thereof for use in the treatment of alternating constipation/diarrhea IBS.
By pharmaceutically acceptable derivative is meant any pharmaceutically acceptable salt or solvate of a 5-HT
3
receptor antagonist or any other compound, which upon administration to the recipient is capable of providing (directly or indirectly) a 5-HT
3
receptor antagonist or an active metabolite or residue thereof.
In one preferred aspect the invention provides a compound of Group A or a pharmaceutically acceptable derivative thereof for use in the treatment of nonconstipated female IBS.
In a further preferred aspect the invention therefore provides alosetron or a pharmaceutically acceptable derivative thereof for use in the treatment of nonconstipated female IBS.
Suitable pharmaceutically acceptable salts of alosetron include acid addition salts formed with inorganic or organic acids (for example hydrochlorides, hydrobromides, sulphates, phosphates, benzoates, naphthoates, hydroxynaphthoates, p-toluenesulphonates, methanesulphonates, sulphamates, ascorbates, tartrates, salicylates, succinates, lactates, glutarates, glutaconates, acetates, tricarballylates, citrates, fumarates and maleates), and solvates (for example hydrates) thereof.
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“new product makes a difference”, M Magnet, The magazine for Glaxo Wellcome plc staff, p. 6, Jul. 1997.
“For Women Only”, rubicon, p. 9, Aug. 1997.
K. Bardhan et al, “A Double-Blind Placebo-Controlled Study to Evaluate The Irritable Bowel Syndrome (IBS)” Gastroenterology, vol. 110, No. 4, Apr. 1996, pp A630.
J Foster et al., “Alosetron Slows Colonic Transit in Patients With Irritable Bowel Syndrome (IBS)” Gastroenterology, vol. 112, 11-14, May 1997, p. A732.
D.G. Maxton et al., “Selective 5-hydroxytryptamine antagonism: a role in irritable bowel syndrome and functional dyspepsia?”, Aliment. Pharmacol. Ther., vol. 10, No. 4, Aug. 1996, pp 595-599.
J. Zighelboim et al.: “Visceral Perception in Irritable Bowel Syndrome”, Dig.Sis.Sci., vol. 40, No. 4, Apr. 1995, pp 819-827.
C.J. Steadman et al., “Selective 5-Hydroxytryptamine Type 3 Receptor Antagonism with Ondansetron as Treatment for Diarrhea-Predominant Irritable Bowel Syndrome: A Pilot Study”, Mayo Clinic Proc., vol. 67, No. 8, Aug., 1992 pp. 732-738.
P.H. Hsyu et al, “Safety and Age, Gender, and Time Dependent Pharmacokinetics of Alosetron”, Pharmaceutical Research, vol. 12, No. 9 Suppl., Sep. 1995, p. S387.
M. Delvaux et al., “Effect of alosetron on responses to colonic distension in patients with irritable bowel syndrome”, Aliment. Pharmacol. Ther., vol. 12, No. 9, Sep. 1998, pp849-855.
R. Berkow et al., “The Merck Manual of Diag
Mangel Allen Wayne
Northcutt Allison Ruth
Glaxo Wellcome Inc.
Morgan Lorie Ann
Spivack Phyllis G.
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