Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2003-02-04
2004-01-27
Reamer, James H (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
active
06683072
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to methods of treatment for irritable bowel syndrome and nonulcer dyspepsia.
BACKGROUND OF THE INVENTION
Irritable bowel syndrome (IBS) is a common functional disorder of the bowel that has a pronounced effect on quality of life. The syndrome is characterized by an altered regulation of bowel motility, chronic abdominal pain or discomfort, and changes in bowel patterns. The changes in bowel patterns can manifest as loose or more frequent bowel movements, diarrhea, and/or constipation. IBS is divided into four subcategories according to whether the predominant symptom is abdominal pain, diarrhea, constipation, or constipation alternating with diarrhea.
Approximately 15 percent of U.S. adults report symptoms that are consistent with the diagnosis of IBS. Nevertheless, it is estimated that only 25 percent of persons with IBS seek medical care. Studies suggest that those who seek care for IBS are also more likely to have accompanying behavioral and psychiatric problems than are those who do not seek care. In addition, patients diagnosed with IBS are at increased risk for other, non-gastrointestinal functional disorders such as fibromyalgia and interstitial cystitis.
IBS appears to affect three times as many women as men. Whether this difference reflects a true predominance of the disorder among women, or merely because women are more likely to seek medical care, has not been determined.
IBS is the most common diagnosis made by gastroenterologists in the U.S., and accounts for 12 percent of visits to primary care providers. Approximately $8 billion in direct medical costs and $25 billion in indirect costs are spent annually in the U.S for diagnosing and treating IBS. Thus, IBS accounts for a large proportion of annual healthcare costs in the U.S.
Converging evidence indicates that IBS results from altered regulation of gastrointestinal motility and epithelial function, as well as from an altered perception of visceral events. See Mayer et al.,
Digestive Diseases,
19:212-218, 2001. Altered bowel motility, visceral hypersensitivity, psychosocial factors, an imbalance in neurotransmitters, and infection have also been proposed as playing a part in the development of IBS. See Horwitz B et al.,
New Engl J Med,
344:24, 2001.
Current therapies for IBS include behavioral modification and training to gain increased awareness of visceral functions, dietary modifications, and treatment with antidiarrheals (e.g., loperamide), antispasmodics or anticholinergic agents. However, none of these therapies are effective for the long-term alleviation of the multiple symptoms of IBS.
Zelnorm™, a partial agonist of the 5-HT
4
serotonin receptor, has been approved for short-term treatment of abdominal pain, bloating and constipation in women with IBS. However, this drug has not been shown to work in men, and is not indicated for female IBS patients whose symptoms include diarrhea. Also, there are concerns about the safety of long-term use of Zelnorm™. See DeNoon D. et al., WebMD Medical News, Oct. 29, 2002.
Nonulcer dyspepsia (NUD) is another common ftmctional disorder of the bowel. NUD is defined as chronic or recurrent upper abdominal pain or discomfort for a period of more than three months' duration, in the absence of another organic cause. The NUD symptoms must be present for more than 25 percent of the time. See Fisher RS, Parkman HP,
New Engl J Med
1998; 339: 1376-1381. NUD has also been characterized as “persistent or recurrent upper abdominal pain or discomfort with no structural or biochemical explanation for the patient's symptoms.” See Locke GR,
Mayo Clin Proc
1999;74:1011-15. Other symptoms associated with NUD include bloating, nausea, early satiety, eructation and heartburn.
NUD has many similarities to IBS. In fact, patients presenting with idiopathic gastrointestinal pain fall into a continuum of functional gastrointestinal disorders which include NUD and IBS. See Freidman LS,
New Engl J Med
1998; 339: 1928-30. NUD and IBS are usually differentiated by determining whether the abdominal pain reported by the patient is associated with abnormal bowel habits. If such an association is present, the condition is considered to be IBS rather than NUD.
Like IBS, the cause of NUD is not well understood. NUD is most likely caused by an alteration in the perception of sensations arising from the gut. Other possible causes of NUD have been investigated, including
Helicobacter pylori
infection. However, no clear relationship has been established between curing an
H. pylori
infection and improvement of NUD. An alteration in stomach function has also been implicated in NUD. For example, about 25-50% of patients with NUD exhibit slowed emptying from the stomach, which may in part explain the increased occurrence of symptoms after meals.
Current therapies for NUD include dietary modifications, such as eating low-fat meals or smaller, more frequent meals to help reduce the symptoms experienced after eating. Other therapies include administering agents to decrease stomach acid, agents to enhance stomach emptying (prokinetic agents) or antibiotics to treat
H. pylori
infection. Antidiarrheals and antispasmodics prescribed for IBS can also be used to treat NUD. However, similar to IBS, none of these therapies significantly improves the overall symptoms in patients with NUD.
Tianeptine, which has the systematic name 7-[(3-chloro-6,11-dihydro-6-methyl-dibenzo[c,f][1,2] thiazepin-11-yl) amino] heptanoic acid S,S-dioxide, is a tricyclic anti-depressant of the dibenzothiazepine type. Tianeptine is known to have psychostimulant, anti-depressive, analgesic, antitussive, antihistaminic and gastric antisecretory properties. See, e.g., U.S. Pat. No. 3,758,528 of Malen et al. Tianeptine acts as a serotonin reuptake accelerator, in that it increases the presynaptic uptake of serotonin. A sodium salt of tianeptine is currently marketed over-the-counter in Europe under the trademark Stablon®. Tianeptine is used to treat neurotic or reactive states of depression, angiodepressive states with somatic complaints such as digestive problems, angiodepressive states observed in alcoholic detoxification, and asthma. The chemical formula of tianeptine is given below:
Tianeptine
There is a need for agents which are effective in treating IBS and NUD. In particular, there is a need for agents that are appropriate for long-term use in treatment and prevention IBS and NUD, and which treat multiple symptoms or manifestations of these disorders.
SUMMARY OF THE INVENTION
Compounds of formula I can prevent or alleviate symptoms of IBS or NUD. A method of treating IBS or NUD therefore comprises administering an effective amount of at least one compound of formula I, or pharmaceutically acceptable salts thereof, to a subject in need of such treatment. Formula I is:
wherein:
A is a bridge selected from the following radicals: —CH
2
)
m
—, —CH═CH—, —CH
2
)
p
—O—, —CH
2
)
p
—S—, —CH
2
)
p
—SO
2
—, —CH
2
)
p
—NR
1
— and —SO
2
—NR
2
—, and wherein:
m is an integer of from 1 to 3 inclusive;
p is an integer selected from 1 and 2;
R
1
is selected from the group consisting of hydrogen and C
1
-C
5
alkyl; and
R
2
is C
1
-C
5
alkyl;
X and Y are independently selected from the group consisting of hydrogen and halogen;
R and R′ are independently selected from the group consisting of hydrogen and C
1
-C
5
alkyl;
n is an integer from 1 to 12 inclusive, preferably 2-10 inclusive, most preferably 4-8 inclusive; and
* denotes an asymmetric carbon and the bond designated by
indicates that the absolute conformation about the asymmetric carbon can be either (R) or (S) only when all four groups attached to the asymmetric carbon are nonequivalent.
According to one preferred embodiment, A is preferably —SO
2
—NR
2
—, and/or R and R′ are hydrogen.
Definitions
The term “alkyl”, by itself or as part of another substituent means a straight, branched or cyclic chain hydrocarbon radical, including di- and multi-radicals, having the number o
Harris Herbert W.
Kucharik Robert F.
Drinker Biddle & Reath LLP
Reamer James H
Vela Pharmaceuticals, Inc.
LandOfFree
Compositions and methods for treatment of irritable bowel... does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Compositions and methods for treatment of irritable bowel..., we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Compositions and methods for treatment of irritable bowel... will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-3212340