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(12) Patent Application Publication (10) Pub. No.: US 2011/0065797 A1 MAKOVEC Et Al

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(12) Patent Application Publication (10) Pub. No.: US 2011/0065797 A1 MAKOVEC Et Al US 2011 0065797A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2011/0065797 A1 MAKOVEC et al. (43) Pub. Date: Mar. 17, 2011 (54) DELOXIGLUMIDE AND PROTON PUMP Related U.S. Application Data INHIBITORS COMBINATION IN THE TREATMENT OF GASTRONTESTINAL (62) Division of application No. 1 1/424,104, filed on Jun. DSORDERS 14, 2006, now Pat. No. 7,863,330. Publication Classification (75) Inventors: Francesco MAKOVEC, Milano-Lesmo (IT); Massimo (51) Int. Cl. Maria DAMATO, Milano - A 6LX 3L/97 (2006.01) Monza (IT); Antonio GIORDANI, A6IPI/00 (2006.01) Pavia (IT): Lucio Claudio A6IPL/04 (2006.01) ROVATI, Milano - Monza (IT) (52) U.S. Cl. ........................................................ 514/563 (73) Assignee: ROTTAPHARM S.P.A., Milano (57) ABSTRACT (IT) Cholecystokinin-1 (CCK1) receptorantagonists and the com bination of CCK1 receptor antagonists and proton pump (21) Appl. No.: 12/950,603 inhibitors (PPI) for the treatment of patients suffering from gastrointestinal or related disorders that have failed to com (22) Filed: Nov. 19, 2010 pletely respond to conventional acid Suppression therapy. US 2011/0065797 A1 Mar. 17, 2011 DELOXGLUMIDE AND PROTON PUMP variety of other abnormalities (e.g., in gastric accommoda INHIBITORS COMBINATION IN THE tion, antral motility/emptying and antroduodenal coordina TREATMENT OF GASTRONTESTINAL tion) have been identified and considered to be pathophysi DISORDERS ologic, but none is found consistently in all patients. Likewise, attempts to establish an etiologic association between the presence of gastric acid and dyspeptic symptoms 0001. This is a Divisional of application Ser. No. 1 1/424, has been unsuccessful, even when ambulatory pH monitoring 104 filed Jun. 14, 2006, claiming priority, the contents of all of has been employed. Hence, there is no unifying mechanism which are incorporated herein by reference in their entirety underlying the generation of symptoms collectively termed DESCRIPTION "dyspeptic, including upper abdominal/epigastric pain and discomfort, abdominal fullness, bloating, belching/eructa 0002 1. Field of the Invention tion, early satiety, nausea and/or vomiting. 0003. The present invention relates to cholecystokinin-1 (CCK1) receptor antagonists and the combination of CCK1 0010 Upper GI disorders are typically classified by ana receptor antagonists and proton pump inhibitors (PPI) for the tomic region, e.g., those of esophageal origin and those of treatment of patients Suffering from gastrointestinal or related gastroduodenal origin, based on epidemiological evidence disorders that have failed to completely respond to conven pointing to the existence of site-specific clusters of symp tional acid suppression therapy. toms. However, the GI tract's anatomic continuity and inte 0004 2. Background of the Invention grated function in digestion and absorption of nutrients 0005 Physicians have long recognized that conditions makes the separation of symptom clusters by site somewhat affecting the upper gastrointestinal (GI) tract commonly pro artificial. In fact, considering the diaphragm to be ananatomic duce upper abdominal pain, discomfort, abdominal fullness, boundary for defining upper GI disorders, e.g., attributing bloating, early Satiety, nausea, heartburn and regurgitation. symptoms localized above the diaphragm Such as heartburn Such symptoms are typically postprandial and occur either to the esophagus, a thoracic organ, and symptoms localized alone or in combination. Overall, upper GI symptoms, includ below the diaphragm Such as epigastric pain and discomfort ing both dyspeptic-type and reflux-type, affect more than to the stomach, an abdominal organ, is not very useful. For 25% of adults in the Western world and have a significant, example, "heartburn' as the sole or predominant symptom to negative impact on both functional status and sense of indi define gastroesophageal reflux disease (GERD) has very low vidual well-being (Tougas et al., Am J. Gastroenterol. 1999; sensitivity (38%) albeit high specificity (about 90%) (Dent et 94: 2845-2854). Symptoms related to disorders of upper gut al., Gut. 2004, 53(May): Supp. 4:1-24). Rather than occurring function are among the most common, presenting complaints alone as a manifestation of GERD, heartburn is associated in primary-care and GI specialty medical practice. These with epigastric pain in at least two thirds of patients. disorders commonly include GERD (gastroesophageal reflux 0011. A study comparing the treatment strategies of 500 disease), GERD with erosion, NERD (nonerosive reflux dis patients with dyspeptic symptoms (pain or discomfort in the ease), PUD (peptic ulcer disease), FD (functional dyspepsia epigastrium with or without heartburn, regurgitation, nausea, also indicated as nonulcer dyspepsia), diabetic gastroparesis, Vomiting or bloating) shows the difficulty in assessing gastrointestinal ulcers, Zollinger-Ellison syndrome, and patients (H. pylori test-and eradicate versus prompt endos antral G-cell hyperplasia. copy) (Lassenetal, Lancet 2000, 356:455-460). Although the 0006 Conventional acid suppression therapy includes the main entry criterion was epigastric pain or discomfort, which use of antacid agents, pepsin inhibitors, gastric mucosa pro was reported by all patients, 32% had heartburn and/or regur tective agents, anticholine agents for Suppressing the secre gitation as their dominant symptom, which was almost as tion of gastric hydrochloric acid, parasympathetic blocking many patients as had dominant epigastric pain (37%). (See agents, histamine H2 receptor antagonists (hereinafter Lassen et al.) Therefore, the available data indicate that sig referred to as “H2 blockers'), proton pump inhibitors, etc. nificant overlap of symptoms exists in esophageal and gastric 0007 Examples of proton pump inhibitors include Lanso disorders; GERD patients have dyspeptic symptoms and dys prazole (brand names: PrevacidR), Zoton R., U.S. Pat. No. peptic patients have heartburn and/or regurgitation. 4,628,098), Omeprazole (brand names: LosecR), PrilosecR), 0012. It is estimated that 15-19% of the American popu U.S. Pat. Nos. 4,255.431 and 5,693.818), Pantoprazole lation experience symptoms of GERD at least weekly and (brand names: Protonix R, Somac R., U.S. Pat. No. 4,758, 10% or more experience associated dyspeptic symptoms. 579), Rabeprazole (brand names: Aciphex(R), Pariet(R), U.S. (Locke et al., Gastroenterology 1997, 112 (5): 1448-1456) Pat. No. 5,045,552) and AZD-0865 (Holstein et al., Gastro Based on results from the National Ambulatory Medical Care enterology 2004, 126 (4, Suppl 2): Abst M1436). Survey, heartburn and indigestion (dyspepsia) together were 0008 Proton pump inhibitors (PPIs) reduce gastric acid estimated to account for over 1.8 million outpatient clinic secretion by inhibition of the gastric proton pump in parietal visits in the United States during the year 2000 (Russo et al. cells. However, PPIs and other conventional treatments that Gastroenterology 2004, 126:1448-1453). reduce gastric acidity do not adequately address all patients. 0013 Cholecystokinin (CCK) belongs to the group of sub For example, esophagitis may be reduced using proton pump stances known as brain-gut peptides and function as a neu inhibitors, but endoscopy in patients with predominantly ropeptide and as a gut hormone. (Noble et al., Pharmacol. reflux-type symptoms reveals that esophagitis may still exist Rev. 1999, 51(4):745-781; Crawley et al., Peptides 1994, in a minority of patients. 15(4):731-755). It is now evident that at least two different 0009 Moreover, patients with predominantly dyspeptic receptors, namely CCK1 (formerly CCKA or alimentary) and type symptoms often have no identifiable gross or micro CCK2 (formerly CCKB or brain) receptors, mediate CCK scopic lesions in either the esophagus or stomach. Although biological actions. (Noble et al., Pharmacol. Rev., 1999, an anatomic lesion is typically absent in dyspeptic patients, a 51(4):745-781; Woodruff and Hughes, Ann. Rev. Pharmacol. US 2011/0065797 A1 Mar. 17, 2011 1991, 31:469-501). CCK1 receptors are found in peripheral ageal motility has been disclosed as a possible treatment to tissues, including the GI tract. gastroesophageal reflux disease. (Tonini et al., Drugs 2004, 0014 CCK is secreted primarily in response to meals and 64(4): 347-361). International Application Nos. PCT/ plays a well-recognized role in regulating gallbladder con EP2004/050936 and PCT/EP2005/050336 also disclose traction and pancreatic enzyme secretion. Over the last pharmaceutical combinations of a proton pump inhibitor and decade, considerable evidence has emerged to support the a compound that modifies gastrointestinal motility. Both concept that CCK plays an equally important role in the international applications disclose that dexloxiglumide may regulation of motor and sensory functions at various levels of be useful for therapy of irritable bowel syndrome (IBS) or the human upper GI tract. Specifically, the native peptide GERD and may be used to modify gastrointestinal motility. delays gastric emptying, modulates gastric sensory function 0019. However, there is no approved treatment for dyspep (especially in response to fat), increases the rate of meal tic symptoms associated with gastrointestinal disorders. In induced, transient lower esophageal sphincter relaxations addition, there is no convincing evidence that current GI (TLESRs) and affects small bowel and colonic transit. treatments successfully relieve dyspeptic symptoms. While 0015 The CCK1
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