US 20050203190A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2005/0203190 A1 Burgard et al. (43) Pub. Date: Sep. 15, 2005 (54) METHODS OF TREATING Related U.S. Application Data GASTRONTESTINAL TRACT DISORDERS USING SODIUM CHANNEL MODULATORS (62) Division of application No. 10/769,071, filed on Jan. 30, 2004. (75) Inventors: Edward C. Burgard, Chapel Hill, NC (US); Steven B. Landau, Wellesley, (60) Provisional application No. 60/443,731, filed on Jan. MA (US); Matthew Oliver Fraser, 30, 2003. Provisional application No. 60/443,730, Apex, NC (US) filed on Jan. 30, 2003. Provisional application No. 60/480,565, filed on Jun. 20, 2003. Provisional appli cation No. 60/480,598, filed on Jun. 20, 2003. Pro Correspondence Address: visional application No. 60/495,958, filed on Aug. 18, ALSTON & BIRD LLP 2003. BANK OF AMERICA PLAZA 101 SOUTH TRYON STREET, SUITE 4000 Publication Classification CHARLOTTE, NC 28280-4000 (US) (51) Int. Cl. ............................................ A61K 31/137 (52) U.S. Cl. .............................................................. 514/649 (73) ASSignee: Dynogen Pharmaceuticals, Inc., Waltham, MA (57) ABSTRACT The invention relates to methods of using Sodium channel (21) Appl. No.: 11/057,024 modulators, particularly TTX-R sodium channel modulators and/or activity dependent Sodium channel modulators to treat a gastrointestinal tract disorders, particularly inflam (22) Filed: Feb. 11, 2005 matory bowel disorders and irritable bowel syndrome. Patent Application Publication Sep.15, 2005 Sheet 1 of 2 US 2005/0203190 A1 Figure 1. A. lamotrigine Control Control 26A750pA fastslow 5ms slow fast 100 s to 80 is 60 s 5(9 40 5 a S. 20 control slow 100M slow control fast 100M fast Patent Application Publication Sep.15, 2005 Sheet 2 of 2 US 2005/0203190 A1 Figure 2. A. N 1oom ambroxo --- N-ul-M1 2nA 2 secs B. 100 80 60 40 20 M ambroxol US 2005/0203190 A1 Sep. 15, 2005 METHODS OF TREATING GASTRONTESTINAL except when very Severe, is limited to the bowel mucosa. TRACT DISORDERS USING SODIUM CHANNEL The course of this disorder may be continuous or relapsing MODULATORS and may be mild or Severe. Medical treatment primarily includes the use of Salicylate derivatives, glucocorticoster CROSS-REFERENCE TO RELATED oids Such as prednisone or prednisone acetate and anti APPLICATIONS metabolites dependent on the clinical State of the patient. Salicylate derivatives, Such as Sulphazine or meSalamine, are 0001. This application is a divisional of copending U.S. efficacious in patients with mild cases of the disorder. application Ser. No. 10/769,071, filed Jan. 30, 2004; which Glucocorticosteroids and anti-metabolites are efficacious in claims the benefit of U.S. Provisional Application No. patients with moderate or Severe disease but are associated 60/443,731, filed Jan. 30, 2003, U.S. Provisional Applica with a number of side effects. Patients who need chronic tion No. 60/443,730, filed Jan. 30, 2003, U.S. Provisional doses of glucocorticosteroids or anti-metabolites for control Application No. 60/480,565, filed Jun. 20, 2003, U.S. Pro of their disorder eventually undergo removal of the colon visional Application No. 60/480,598, filed Jun. 20, 2003, Surgically to eliminate the disease. and U.S. Provisional Application No. 60/495,958, filed Aug. 18, 2003; the contents of which are herein incorporated by 0007 Like ulcerative colitis, Crohn's disease (also reference in their entirety. known as regional enteritis, ileitis, or granulomatous ileo colitis) is a chronic inflammatory disorder of unknown FIELD OF THE INVENTION etiology; however the location and pathology of the disease differ. Crohn's disease typically presents in either the Small 0002 The invention relates to methods of using sodium intestine, large intestine or the combination of the two channel modulators, particularly TTX-R sodium channel locationsand can cause inflammation deeper into the muscle modulators and/or activity dependent Sodium channel and serosa located within the intestinal wall. The course of modulators, to treat gastrointestinal tract disorders, particu the disorder may be continuous or relapsing and may be mild larly inflammatory bowel disorders and irritable bowel syn or Severe. Medical treatment includes the continuous use of drome. Salicylate derivatives, glucocorticosteroids, anti-metabo lites, and administration of an anti-TNF antibody. Many BACKGROUND OF THE INVENTION Crohn's disease patients require intestinal Surgery for a 0003 Gastrointestinal (GI) tract disorders affect the qual problem related to the disease, but unlike ulcerative colitis ity of life of millions of men and women in the United States Subsequent relapse is common. every year. GI tract disorders may involve disturbances of 0008 Collagenous colitis and lymphocytic colitis are the GI Smooth muscle, epithelium, Sensory afferent neurons, idiopathic inflammatory disorders of the colon that cause or central nervous System pathways. In Spite of the uncer watery diarrhea typically in middle-aged or older individu tainty regarding whether central or peripheral mechanisms, als. Lymphocytic colitis is distinguished from collagenous or both, are involved in GI tract disorders, many proposed colitis by the absence of a thickened Subepithelial collag mechanisms implicate neurons and pathways that mediate enous layer. Bismuth in the form of Pepto-Bismol may be an Visceral Sensation. Viscerosensory information from the GI effective treatment in Some patients, although more Severe tract is relayed by Sensory fibers that enter the Spinal cord via cases may require the use of Salicylate derivatives, antibi the dorsal root ganglion (DRG) or project to the nodose otics Such as metronidazole, and glucocorticosteroids. ganglion via Vagal afferents (Physiology, ed. R. M. Berne and M. N. Levy, 1983, CV Mosby Co. St. Louis). A number of 0009 Functional GI tract disorders are characterized by different Subtypes of Sensory afferent neurons may be presentation of abdominal-type Symptoms without evidence involved in neurotransmission from the GI tract. These may of changes in metabolism or Structural abnormalities. Dis be classified as, but not limited to, Small diameter, medium orders that are typically considered under functional disor diameter, large diameter, myelinated, unmyelinated, Sacral, ders include dysphagia, non-ulcer dyspepsia, irritable bowel lumbar, DRG, Vagal, nodose, peptidergic, non-peptidergic, Syndrome, Slow-transit constipation, and evacuation disor IB4 positive, IB4 negative, C fiber, Aö fiber, AB fiber, high ders (Camilleri (2002) Gastrointestinal Motility Disorders, threshold or low threshold neurons. In WebMDScientific American Medicine, edited by David C. Dale and Daniel D. Federman, New York, N.Y., WebMD). A 0004 GI tract disorders have been characterized as struc prominent example of a functional GI tract disorder is tural (or mucosal) GI tract disorders and non-structural (or irritable bowel syndrome (IBS), also known by a variety of non-mucosal) GI tract disorders. Structural disorders include Synonyms, including functional bowel, pylorospasm, ner inflammatory bowel disorders and non-inflammatory Struc Vous indigestion, Spastic colon, Spastic colitis, Spastic tural GI tract disorders. Non-structural disorders include a bowel, intestinal neurosis, functional colitis, irritable colon, variety of disorders classified as functional GI tract disor mucous colitis, laxative colitis, and functional dyspepsia. derS. IBS generally leads to abdominal pain and/or discomfort and 0005 Inflammatory bowel disorders include a group of an alteration in bowel habit with no clear etiology. Diagnosis disorders that can cause inflammation or ulceration of the GI relies on Rome criteria taking into account all Symptoms tract. Ulcerative colitis and Crohn's disease are the most related to patient presentation. (See, e.g., Drossman et al. common types of inflammatory bowel disorders, although (1997) Gastroenterology, 112. 2120). Patients typically collagenous colitis, lymphocytic (microscopic) colitis, and present with Symptoms consistent with hyperalgesia and other disorders have also been described. allodynia. 0006 Ulcerative colitis is a chronic inflammatory disor 0010. At present, treatments for IBS have been largely der of unknown etiology afflicting the large intestine and, ineffective, and have included StreSS management, diet, and US 2005/0203190 A1 Sep. 15, 2005 drugs. Psychoactive drugs, Such as anxiolytics and antide Diverticulosis is a disorder that rarely occurs in the Small preSSants, have been utilized but have limited utility because intestine and most commonly appears in the colon. of the Side effect profile. Antispasmodics and various antidi 0014. Because existing therapies and treatments for GI arrheal preparations have also been used but these remain as tract disorders are associated with limitations as described unsatisfactory remedies to patients with IBS. above, new therapies and treatments are therefore desirable. 0011 Non-ulcer dyspepsia (NUD) is another prominent example of a functional GI tract disorder with no established SUMMARY OF THE INVENTION etiology. Symptoms related to NUD include nausea, vom 0015 Compositions and methods for treating GI tract iting, pain, early Satiety, bloating and loSS of appetite. disorders, particularly inflammatory bowel disorders and Altered gastric emptying and increased gastric Sensitivity irritable bowel syndrome, are provided. Compositions of the and distress may contribute to NUD but do not completely