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 antagonists loxiglumide and dexloxiglu there is compelling evidence for the effectiveness of acid mide have demonstrated the ability to reverse the physiologic Suppression therapy in patients with symptomatic heartburn effects of CCK on gastric emptying and to decrease dyspeptic and/or regurgitation due to GERD, there is a lack of convinc symptoms induced by air distension and fat infusion. By ing evidence of the effectiveness of acid Suppression therapy example, loxiglumide reduced both exogenous and endog for dyspeptic symptoms associated with GERD. Indeed, it is enous CCK-induced delay in gastric emptying of liquids and a frequent observation that the majority of patients treated solids in healthy subjects (Borovicka et al., Am J. Physiol. with a PPI for GERD symptoms are left with residual dys 1996, 271:448-453; Schwizer et al., Gut. 1997, 41(4):500 peptic symptoms. 504). Dexloxiglumide reversed the diminished tolerance to 0020 Since current acid suppression treatment options for water volume that occurred from CCK release in response to gastrointestinal disorders with dyspepsia type symptoms do duodenal lipid infusion; the effect was due to reduction of not adequately address the complexities of these diseases, intragastric Volume, primarily due to accelerated gastric emp there remains a need for a treatment that is effective in at least tying (Lal et al., Am J Physiol Gastrointest Liver Physiol. a Substantial portion of this patient population, without pro 2004,287(1):72-79). When proximal gastric relaxation was ducing severe adverse effects. produced in healthy subjects by duodenal infusion of lipid, a potent stimulus of CCK release, the relaxation was reversed SUMMARY OF THE INVENTION by loxiglumide (Feinle et al., Gastroenterology 1996,110(5): 0021. The present invention relates to cholecystokinin-1 1379-1385). Also, loxiglumide modulated antro-py (CCK1) receptor antagonists and the combination of CCK1 loroduodenal dysmotility, which is postulated to play a role in receptor antagonists and proton pump inhibitors (PPI) for the generation of dyspeptic symptoms, after it was experimen treatment of patients suffering from gastrointestinal or related tally induced in healthy subjects by intraduodenal infusion of disorders that have failed to completely respond to conven a mixed liquid meal (Katschinski et al., Eur J. Clin Invest. tional acid Suppression therapy. The present invention 1996, 26(7):574-583). Loxiglumide was also able to reverse describes for the first time that the clinical administration of a the lowering of intragastric pressure of healthy Subjects after CCK1 antagonist is effective for the treatment of patients duodenal infusion of lipids induced sensations such as full Suffering from gastrointestinal or related disorders whom ness and nausea (See Feinle et al., 1996). have failed to completely respond to conventional acid Sup 0016. In patients with nonulcer dyspepsia and delayed pression therapy. Moreover, these patients may demonstrate gastric emptying, loxiglumide was shown to accelerate gas unexpected improvement in residual dyspeptic-type symp tric emptying by comparison to placebo (Chua AS, Bekker tOmS. ing M. et al., 1994). Loxiglumide significantly improved 0022. In one embodiment, the invention relates to a dyspeptic symptoms in patients with non-ulcer dyspepsia in method of treating gastrointestinal disorders comprising an 8-week study (Chua et al., Ann NY Acad. Sci. 1994, administering to a patient failing to completely respond to 713:298-299). In another study in patients with functional conventional acid suppression therapy a CCK1 receptor dyspepsia, aggravation of nausea, fullness, discomfort, bloat antagonist in an amount effective to treat the gastrointestinal ing and pain was produced by duodenal infusion of lipid with disorder. For example, the Subjects being treated may not be or without balloon distension; dexloxiglumide significantly completely responsive to conventional acid suppression improved dyspepsia symptom scores compared to placebo therapy and are suffering from GERD (Gastroesophageal (Feinle et al., Gut. 2001, 48(3): 347-355). Reflux Disease), GERD with erosion, NERD (NonErosive 0017 Pharmaceutical compositions comprising CCKB Reflux Disease), PUD (Peptic Ulcer Disease), FD (Func antagonists and a proton pump inhibitor to control gastric tional Dyspepsia), Diabetic Gastroparesis, Nocturnal heart acid secretion in gastrointestinal disorders have been burn, Heartburn, Bloating, gastrointestinal ulcers, Zollinger described in the literature. (See WO 04/098610, WO Ellison syndrome and antral G-cell hyperplasia. 04/101533, WO 04/098609, WO 03/041714, WO 01/90078, 0023. In another embodiment, the invention relates to WO 01/85724, WO 01/85723, WO 01/85704, WO 01/85167, pharmaceutical compositions for treating gastrointestinal and WO 93/12817) CCK-B receptors mediate CCK biologi disorders of patients failing to completely respond to conven cal actions in the brain and are one of several regulators of tional acid suppression therapy comprising: (i) a CCK1 gastric acid secretion. It is the CCK1 receptors, however, that receptor antagonist; and (ii) a pharmaceutically acceptable mediate the CCK biological actions in peripheral tissues carrier or excipient, wherein the CCK1 receptor antagonist is including gastric emptying and esophageal sphincter effects. present at a therapeutically effective dosage. 0018. In addition, combination therapy of a PPI and a 0024. In another embodiment, the invention relates to a second agent, e.g., loxiglumide, to improve impaired esoph method of treating a gastrointestinal disorder comprising US 2011/0065797 A1 Mar. 17, 2011 administering to a patient in need of Such treatment a first 0030 Alkoxy' means an alkyl-O-group: non-limiting amount of a CCK1 receptor antagonist and a second amount examples of suitable alkoxy groups include methoxy, ethoxy, of a proton pump inhibitor (PPI), the first and second amounts n-propoxy, isopropoxy and butoxy. The alkyl group is linked in combination being effective at improving at least one to an adjacent moiety through the ether oxygen. symptom from the gastrointestinal disorder. 0031. The compounds of Formula I can be administered as 0025. In another embodiment, the invention relates to racemic mixtures or enantiomerically pure compounds pharmaceutical compositions for treatment of gastrointesti nal disorders comprising: (i) a CCK1 receptor antagonist; (ii) within the scope of the present invention. a proton pump inhibitor (PPI); and (iii) a pharmaceutically 0032. The compounds of Formula I can form salts and acceptable carrier or excipient, wherein the CCK1 receptor solvates that are also within the scope of this invention. antagonist is present at a therapeutically effective dosage. 0033 “Solvate” means a physical association of a com pound of this invention with one or more solvent molecules. DETAILED DESCRIPTION OF THE INVENTION This physical association involves varying degrees of ionic and hydrogen bonding. Solvates of the compounds of the 0026. The present invention relates to cholecystokinin-1 invention are also contemplated as within the scope of the (CCK1) receptor antagonists and the combination of CCK1 present invention. Reference to a compound of Formula I receptor antagonists and proton pump inhibitors (PPI) for the herein is understood to include reference to salts and solvates treatment of patients Suffering from gastrointestinal or related thereof, unless otherwise indicated. disorders that have failed to completely respond to conven tional acid suppression therapy. Preferably, the CCK1 recep 0034. Within the meaning of the present invention, the tor antagonist and proton pump inhibitor are administered at term “visceral' is used in its broadest sense to refer to organs therapeutically effective dosages which, when combined, that are located in the trunk of the body, e.g., the heart, liver, provide a beneficial effect. intestines. 0027. At least ten classes of CCK1 receptor antagonists 0035. The terms “gut motility”, “gastric motility”, “GI are now available (DAmato et al., Exp. Opin. Invest. Drugs motility”, and “intestinal motility” are used interchangeably 1997, 6(7):819-836). The amino acid derivative CCK recep to refer generally to the peristaltic movements of the gas torantagonist proglumide was discovered more than 20 years trointestinal tract. These terms are also used more specifically ago by Rotta Research Laboratorium SpA. However, it has to refer to contractions of the smooth muscle of the intestine, low potency and specificity (the compound also effectively which result in propelling intestinal contents through the gut binds CCK2 receptors). More recently synthesized glut (the process termed “peristalsis). aramic acid derivatives, lorglumide and loxiglumide (both 0036. The term “combination' applied to active ingredi from Rotta Research Laboratorium SpA), are potent, specific ents is used herein to define a single pharmaceutical compo competitive antagonists of CCK1 receptors. They are active sition (formulation) comprising both drugs of the invention after oral administration and are able to antagonize the effects (i.e., a CCK1 receptor antagonist and a proton pump inhibi of both endogenous and exogenous CCK. These selective tor) or two separate pharmaceutical compositions (formula CCK1 receptor antagonists are effective in increasing GI tions), each comprising a single drug of the invention (i.e., a motility. CCK1 receptorantagonistora proton pump inhibitor) and are 0028 Dexloxiglumide (R-4-(3,4-dichlorobenzoy administered conjointly. lamino)-5-(N-3-methoxypropyl-pentylamino)-5-oxo-pen 0037. Within the meaning of the present invention, tanoic acid), the (R)-isomer ofloxiglumide, is approximately “administered conjointly' is used to refer to administration of twice as potent as the racemic compound, because the anti a CCK1 receptor antagonistand proton pump inhibitor simul CCK activity resides in the (R)-form (see D'Amato et al., taneously in one composition, or simultaneously in different 1997). Dexloxiglumide has been developed by Rotta compositions, or sequentially. For the sequential administra Research Laboratorium SpA for the treatment of diseases in tion to be considered “conjoint, the CCK1 receptor antago which CCK1 receptor activity is potentially involved, includ nist and proton pump inhibitor must be administered sepa ing gastrointestinal motility, food intake and pancreatic dis rated by a time interval that permits the resultant beneficial orders (Varga et al., Curr. Opin. Investig. Drugs 2002, 3(4): effect for treating, preventing, arresting, delaying the onset of 621-626). Results from both preclinical and clinical studies and/or reducing the risk of developing in a mammal a gut indicate that dexloxiglumide is an effective inhibitor of gall motility disorder associated with gastrointestinal or related bladder contraction, improves lower esophageal sphincter disorders. For example, within the meaning of the present (LES) function, accelerates gastric emptying, and accelerates invention the CCK1 receptor antagonist and proton pump colonic transit, and therefore has potential as an effective inhibitor may be administered on the same day (e.g., each— treatment for gastrointestinal and related disorders (Scarpig once or twice daily), preferably within an hour of each other, nato et al., J. Physiol. Paris 1993, 87(5):291-300; See and most preferably simultaneously. D'Amatoet al., 1997: Feinie et al., Gut 2001, 48(3):347-355). 0038. The term “treating is used hereinto mean to relieve, alleviate, delay, reduce or prevent at least one symptom of a DEFINITIONS disease in a Subject. For example, in relation to a gastrointes tinal disorder, the term “treat may mean to relieve or allevi 0029. Except where stated otherwise, the following defi ate at least one symptom that includes, but is not limited to, nitions apply throughout the present specification and claims. increased tension on the wall of the stomach, increased intra These definitions apply regardless of whether a term is used visceral pressure, cramps, colitis, gnawing, abdominal pain, by itself or in combination with other terms. Hence the defi constipation, diarrhea, nausea, vomiting, urge to defecate, nition of “alkyl applies to “alkyl as well as to the “alkyl tenesmus, hematochezia, etc. Within the meaning of the portions of “alkoxy.” present invention, the term “treat also means to arrest, delay US 2011/0065797 A1 Mar. 17, 2011

the onset (i.e., the period prior to clinical manifestation of a disease) and/or reduce the risk of developing or worsening a disease. COOH 0039 For example, as disclosed herein, a prophylactic administration of a CCK1 receptor antagonist in combination ICH2 with a proton pump inhibitor can protect a recipient Subject at risk of developing a gastrointestinal disorder. Similarly, (*) HC-N-C-RH || according to the present invention, a therapeutic administra O R2 tion of a CCK1 receptor antagonist conjointly with a proton A pump inhibitor can lead to slow-down in the development of CO-N clinical symptoms or even regression of symptoms. 0040. Within the meaning of the present invention, the th- CH term “proton pump inhibitor is used to refer to compounds that can Suppress the function of the hydrogen-potassium wherein: adenosine triphosphatase enzyme system to reduce the I0045) R' is selected from the group consisting of 2-naph release of acid in the stomach and intestines. thyl, 3,4-dichlorophenyl and 3,4-dimethylphenyl: 0041. Inhibitors of H' KATPase (proton pump) can 10046 R is a pentyl group or an alkoxyalkyl group with 4 bind irreversibly or reversibly to the enzyme. Agents referred carbonatoms; and pharmaceutically acceptable salts thereof. to as Proton Pump Inhibitors (PPIs) typically include irrevers 0047. The compounds of the present invention include ible inhibitors. The most commonly known irreversible pro enantiomers, hydrates and mixtures of the compounds of ton pump inhibitors include: Omeprazole (brand names: Formula (I). For example, the substituents on the chiral cen LosecR), PrilosecR), Lansoprazole (brand names: Prevacid R, ter, marked with an asterisk in formula (I), may have the R Zoton(R), Esomeprazole (brand names: Nexium(R), Panto (rectus) or R,S (Rectus, Sinister) conformation. Preferably, the substituents on the central chiral group have the R (rectus) prazole (brand names: Protonix R, SomacR) and Rabeprazole conformation. (brand names: Aciphex(R), ParietR). These irreversible PPIs 0048 Exemplary CCK1 receptor antagonists according to contain a Sulfinyl group situated between the benzoimidazole the present invention include, but are not limited to: and pyridine rings. Though, at neutral pH, omeprazole, lan 0049. Dexloxiglumide (R-4-(3,4-dichlorobenzoy soprazole, rabeprazole and pantoprazole are chemically lamino)-5-(N-3-methoxypropyl-pentylamino)-5-oxo stable, lipid soluble and devoid of inhibitory activity, at acidic pentanoic acid); pH these compounds rearrange to form a Sulfenic acid and a 0050. Loxiglumide (RS-4-(3,4-dichlorobenzoylamino)- Sulfenamide. These formed species are capable to interact 5-(N-3-methoxypropyl-pentylamino)-5-oxo-pentanoic with sulfhydryl groups of the enzyme and provide irreversible acid); inhibition. 0051 Lorglumide (RS-4-(3,4-Dichlorobenzoyl)amino 0042. Reversible inhibitors are also referred to as Acid 5-(dipentylamino)-5-oxopentanoic acid); Pump Antagonists (APAs). APAS differ from the classical 0.052 Amiglumide ((R)-4-(2-Naphthamido)-N,N-dipen PPIs listed above in the way they inhibit H KATPase. For tylglutaramic acid); as well as polymorphs, Solvates, phar example, acid induced transformation is not necessary for maceutically acceptable salts, and mixtures thereof. activation and enzyme kinetics typically shows reversible 0053 Various salts and isomers (including stereoisomers binding to the enzyme for APAS. Examples of suitable APAS and enantiomers) of the drugs listed herein can be used. The include, but are not limited to, CS-526 (Sankyo), AZD0865 nature of the salt or isomer is not critical, provided that it is (Astra Zeneca), Soraprazan (Altana AG); other APAS are non-toxic and does not substantially interfere with the desired described by Sachs et al. U.S. Pat. No. 6,132,768, the disclo pharmacological activity. sure of which is hereby incorporated by reference in its 0054 For example, pharmaceutically acceptable base entirety. Accordingly, within the meaning of the present addition salts are formed with metals oramines, such as alkali invention, the term “proton pump inhibitor includes all the and alkaline earth metals or organic amines. Examples of compounds that can suppress H-KATPase activity acting metals that may be used as cations include sodium, potas either as irreversible or reversible inhibitors. sium, magnesium, calcium, and the like. Examples of suitable 0043. The terms “cholecystokinin-1 (CCK1) receptor amines include N,N'-dibenzylethylenediamine, choline, antagonist or "CCK1 receptor antagonist drugs' are used to diethanolamine, dicyclohexylamine, ethylenediamine and refer to compounds that can Suppress the normal function of N-methylglucamine. CCK1 receptor, such as referred CCK1 receptor antagonist 0055 As used herein the term “therapeutically effective” drugs of the invention are derivatives of glutamic acid, most applied to dose or amount refers to that quantity of a com preferably derivatives of (R) 5-pentylamino-5-oxopentanoic pound or pharmaceutical composition that is sufficient to acid, such as Dexloxiglumide. result in a desired activity upon administration to a mammal 0044) The CCK1 receptor antagonists of the present in need thereof. More specifically, the term “therapeutically invention are glutamic acid derivatives, namely 5-penty effective' refers to that quantity of a compound or pharma lamino-5-oxopentanoic acid derivatives. These derivatives ceutical composition that is sufficient to reduce or eliminate at and methods for their preparation are disclosed in U.S. Pat. least one symptom of a gastrointestinal disorder. Nos. 4,769,389, 4,880,938 and 5,130,474, the disclosures of 0056. The phrase “pharmaceutically acceptable', as used which are hereby incorporated by reference in their entirety. in connection with compositions of the invention, refers to The glutamic acid derivatives of the present invention can be molecular entities and other ingredients of Such compositions represented by the general formula (I): that are physiologically tolerable and do not typically pro US 2011/0065797 A1 Mar. 17, 2011

duce untoward reactions when administered to a mammal 0060 For liquid preparations the oral administration can (e.g., a human). Preferably, as used herein, the term “phar take the form of for example, Solutions, syrups, emulsions or maceutically acceptable” means approved by a regulatory Suspensions, or they can be presented as a dry product for agency of the Federal or a state government or listed in the reconstitution with water or other suitable vehicle before use. U.S. Pharmacopeia or other generally recognized pharma Preparations for oral administration can be suitably formu lated to give controlled or postponed release of the active copeia for use in mammals, and more particularly in humans. compound. 0057 The term “carrier applied to pharmaceutical com 0061 The active drugs can also be administered in the positions of the invention refers to a diluent, excipient, or form of liposome delivery systems, such as Small unilamellar vehicle with which an active compound is administered. Such vesicles, large unilamellar vesicles and multilamellar pharmaceutical carriers can be sterile liquids, Such as water, vesicles. Liposomes can be formed from a variety of phos saline Solutions, aqueous dextrose solutions, aqueous glyc pholipids, such as cholesterol, Stearylamine orphosphatidyl erol solutions, and oils, including those of petroleum, animal, cholines, as is well known. Vegetable or synthetic origin, such as peanut oil, soybean oil, 0062 Active drugs may also be coupled with soluble poly mineral oil, Sesame oil and the like. Suitable pharmaceutical mers as targetable drug carriers. Such polymers can include excipients also include binding agents (e.g., pregelatinized polyvinyl-pyrrolidone, pyran copolymer, polyhydroxy-pro maize starch, polyvinylpyrrolidone or hydroxypropyl meth pyl methacrylamide-phenol, polyhydroxy-ethyl-asparta ylcellulose); fillers (e.g., lactose, Sucrose, glucose, mannitol, mide-phenol, or polyethyleneoxide-polylysine Substituted Sorbitol and other reducing and non-reducing Sugars, micro with palmitoyl residues. crystalline cellulose, calcium Sulfate, or calcium hydrogen 0063. Furthermore, active drug may be coupled to a class phosphate); lubricants (e.g., magnesium Stearate, talc, or of biodegradable polymers useful in achieving controlled silica, steric acid, sodium Stearyl fumarate, glyceryl behenate, release of a drug, for example, polylactic acid, polyglycolic calcium Stearate, and the like), disintegrants (e.g., potato acid, copolymers of polylactic and polyglycolic acid, poly starch, Sodium starch glycolate, crosslinked carboxymethyl epsilon caprolactone, polyhydroxybutyric acid, polyorthoe cellulose sodium or crosslinked povidone); or wetting agents sters, polyacetals, polyhydropyrians, polycyanoacrylates, and (e.g., Sodium lauryl Sulphate), coloring and flavoring agents, cross-linked or amphipathic block copolymers of hydrogels. gelatin, Sweeteners, natural and synthetic gums (such as aca 0064. The formulations of the invention can be delivered cia, tragacanth or alginates), buffer salts, carboxymethylcel parenterally, e.g., by intravenous (i.v.). Subcutaneous (s.c.), lulose, polyethyleneglycol, waxes, inert carriers (e.g., etha intramuscular (i.m.), subdermal (s.d.), or intradermal (i.d.) nol, glycerol, water), Suspending agents (e.g., Sorbitol syrup, administration, by direct injection, Via, for example, bolus cellulose derivatives or hydrogenated edible fats), emulsify injection or continuous infusion. Formulations for injection ing agents (e.g., lecithin or acacia), non-aqueous vehicles can be presented in unit dosage form, e.g., in ampoules or in (e.g., almond oil, oily esters, ethyl alcohol or fractionated multi-dose containers, with an added preservative. The com Vegetable oils), preservatives (e.g., methyl or propyl-p-hy positions can take Such forms as excipients, Suspensions, droxybenzoates or sorbic acid), and the like. For other Solutions, or emulsions in oily or aqueous vehicles, and can examples see “Remington's Pharmaceutical Sciences” by E. contain formulatory agents such as Suspending, stabilizing W. Martin, 18th Edition, the disclosure of which is hereby and/or dispersing agents. Alternatively, the active ingredient incorporated by reference in its entirety. can be in powder form for reconstitution with a suitable 0058. The active agents of the present invention may be vehicle, e.g., sterile pyrogen-free water, before use. administered orally, topically, parenterally, or mucosally 0065. As disclosed herein, a proton pump inhibitor and (e.g., buccally or rectally) in dosage unit formulations con CCK1 receptor antagonist can be mixed with excipients that taining conventional non-toxic pharmaceutically acceptable are pharmaceutically acceptable and compatible with the carriers. In preferred embodiments, the active agents of the active ingredients. In addition, if desired, the preparations present invention may be administered orally. For example, may also include minor amounts of auxiliary Substances Such the active agents may be administered orally in the form of a as wetting or emulsifying agents, pH buffering agents, and/or capsule or a tablet (see Remington's Pharmaceutical Sci agents that enhance the effectiveness of the pharmaceutical ences, Mack 5 Publishing Co., Easton, Pa.). The orally composition. administered medicaments may be administered in the form 0.066 Although the active agents of the present invention of a modified release formulation or device, including diffu may be administered in divided doses, for example, two or Sion-controlled systems, osmotic devices, dissolution-con three times daily, a single daily dose is preferred, with a single trolled matrices, and erodible/degradable matrices. daily dose of both agents in one composition or in two sepa 0059 For oral administration in the form of a tablet or rate compositions administered simultaneously being most capsule, the active drug component can be combined with a preferred. non-toxic, pharmaceutically acceptable excipients such as 0067. The instant invention also encompasses a process binding agents, fillers, lubricants, disintegrants, coloring and for preparing pharmaceutical compositions comprising com flavoring agents, gelatin, Sweeteners, natural and synthetic bining a CCK1 receptor antagonist and/or a proton pump gums, buffer salts, carboxymethylcellulose, polyethyleneg inhibitor with a pharmaceutically acceptable carrier and/or lycol and waxes. For oral administration in liquid form, the excipient. drug components can be combined with non-toxic, pharma 0068 Preferred specific amounts of the proton pump ceutically acceptable inert carriers, Suspending agents, emul inhibitor that may be used in unit dosage amounts of the Sifying agents, non-aqueous vehicles and preservatives. Sta invention include, for example, about 1 to 60 mg, preferably bilizing agents such as antioxidants (e.g., BHA, BHT propyl about 5 to 50 mg and more preferably about 10 to 40 mg. gallate, Sodium ascorbate, and citric acid) can also be added to Preferred specific amounts of the CCK1 receptor antagonist stabilize the dosage forms. which may be used in unit dosage amounts of the invention US 2011/0065797 A1 Mar. 17, 2011 include, for example, about 10 to 1000 mg, preferably about 0074 For any pharmaceutical composition used in the 50 to 600 mg and more preferably about 100 to 400 mg. methods of the invention, the therapeutically effective dose 0069. The invention also provides a pharmaceutical pack can be estimated initially from animal models to achieve a or kit comprising one or more containers containing one or circulating plasma concentration range that includes the IC50 more of the ingredients of the formulations of the invention. (i.e., the concentration of the test compound which achieves a In a related embodiment, the present invention provides a kit half-maximal inhibition). Dose-responsecurves derived from for the preparation of the pharmaceutical compositions of the animal systems may then be used to determine testing doses invention, said kit comprising a CCK1 receptor antagonist in for the initial clinical studies in humans. In safety determina a first container, and a proton pump inhibitor in a second tions for each composition, the dose and frequency of admin container, and, optionally, instructions for admixing the two istration should meet or exceed those anticipated for use in the drugs and/or for administration of the compositions. Each clinical trial. container of the kit may also optionally include one or more (0075. As disclosed herein, the dose of the CCK1 receptor physiologically acceptable carriers and/or excipients and/or antagonist in the compositions of the present invention is auxiliary Substances. Associated with Such container(s) can determined to ensure that the dose administered continuously be a notice in the form prescribed by a governmental agency or intermittently will not exceed an amount determined after regulating the manufacture, use or sale of pharmaceuticals or consideration of the results in test animals and the individual biological products, which notice reflects approval by the conditions of a patient. A specific dose naturally varies (and is agency of manufacture, use or sale for human administration. ultimately decided according to the judgment of the practi 0070 The compositions may, if desired, be presented in a tioner and each patient's circumstances) depending on the pack or dispenser device that may contain one or more unit dosage procedure, the conditions of a patient or a subject dosage forms containing the active ingredient. The pack may, animal Such as age, body weight, sex, sensitivity, feed, dosage for example, comprise metal or plastic foil. Such as a blister period, drugs used in combination, seriousness of the disease, pack. The pack or dispenser device may be accompanied by etc. For example, an appropriate dose of a CCK1 receptor instructions for administration. Compositions of the inven antagonist is generally in the range of about 1 to about 20 mg tion formulated in a compatible pharmaceutical carrier may per kg of the body weight. also be prepared, placed in an appropriate container, and 0076 Toxicity and therapeutic efficacy of the composi labeled for treatment of an indicated condition. The compo tions of the invention may be determined by standard phar sitions of the invention may be administered in a modified maceutical procedures in experimental animals, e.g., by release formulation. Modified release dosage forms provide a determining the LD50 (the dose lethal to 50% of the popula means for improving patient compliance and for ensuring tion) and the ED50 (the dose therapeutically effective in 50% effective and safe therapy by reducing the incidence of of the population). The dose ratio between therapeutic and adverse drug reactions. Compared to immediate release dos toxic effects is the therapeutic index and can be expressed as age forms, modified release dosage forms can be used to the ratio ED50/LD50. Compositions that exhibit large thera prolong pharmacological action after administration, and to peutic indices are preferred. reduce variability in the plasma concentration of a drug 0077. The data obtained from animal studies may be used throughout the dosage interval, thereby eliminating or reduc in formulating a range of doses for use in humans. The doses ing sharp peaks. of derivatives used in humans are preferably within a range of 0071. The majority of modified release dosage forms com circulating concentrations that include the ED50 with little or prise a core either coated with or containing a drug. The core no toxicity. The dosage can vary within this range depending may be coated with a release-modifying polymer within upon the dosage form employed and the route of administra which the drug is dispersed. The release-modifying polymer tion utilized. may then disintegrate gradually, releasing the drug over time. 0078. The drug combinations of the invention are not only Thus, the outer-most layer of the composition effectively highly effective at relatively low doses but also possess low slows down and thereby regulates the diffusion of the drug toxicity and produce few side effects. Indeed, the most com across the coating layer when the composition is exposed to mon side effect resulting from the use of a CCK1 receptor an aqueous environment, i.e. the gastrointestinal tract. The antagonist and a proton pump are mild and transient nausea, net rate of diffusion of the drug is mainly dependent on the diarrhea, abdominal pain, malaise, and increased appetite. ability of the gastric fluid to penetrate the coating layer or 007.9 The following examples are merely illustrative of matrix and on the solubility of the drug itself. the present invention and should not be construed as limiting 0072 According to the methods of the present invention, the scope of the invention in any way as many variations and the pharmaceutical compositions are administered to a equivalents that are encompassed by the present invention patient at therapeutically effective doses, preferably, with will become apparent to those skilled in the art upon reading minimal toxicity. Preferably, the proton pump inhibitor and the present disclosure. the CCK1 receptor antagonist are each used at a dosage which, when combined, provide an enhanced effect, most Preclinical Studies preferably, an effect not observed upon administration of each agent alone. Effect on Acute Reflux Esophagitis in Rats 0073. The efficacy of a CCK1 receptor antagonist or PPI 0080 Male rats of 175-200 g body weight were fasted for was determined in preclinical studies using Small animal 24 hours prior the experiment. Water was allowed ad libitum. models (e.g., rats) in which both the CCK1 receptor antago Under ether anesthesia, the abdomen was incised along the nist and proton pump inhibitor have been found to be thera midline, and both pylorus and limiting ridge (transitional peutically effective and in which these drugs can be admin region between the forestomach and corpus) were simulta istered by the same route proposed for the human clinical neously ligated. Consequently, the total capacity of the stom trials. ach to hold gastric juice was greatly diminished, resulting in US 2011/0065797 A1 Mar. 17, 2011

reflux of gastric juice into the esophagus. Following ligation pepsia (FD) and received an adequate dose of a PPI for at least of pylorus and limiting ridge, the test compounds were given 4 weeks within the preceding 12 months. Only patients who intraduodenally (5 ml/kg), and the abdomen was closed by continue to experience symptoms of FD while on an adequate suturing. After 3 hours, rats were killed by ether overdose and course of treatment with a proton pump inhibitor (PPI) will be the gastroesophageal portion was excised. The lesion in the eligible for enrollment. The synopsis below describes the thoracic esophagus was scored macroscopically, using a study in further detail. lesion index according to the following criteria: no lesion as I0085. An 8-week treatment, prospective, randomized, 0; edema as 1; reddening as 2; the length of hemorrhagic area double-blind, placebo-controlled, single-dose, parallel <20 mm as 3; the length of hemorrhagic area 20-30 mm as 4: group, multicenter study will be performed to investigate the the length of hemorrhagic area 30-40 mm as 5; the length of safety and efficacy of dexloxiglumide 300 mg b.i.d. for the hemorrhagic area >40 mm or perforation as 6. relief of dyspeptic symptoms in patients being treated with 0081. The doses of the tested compounds which reduce of proton pump inhibitors. 50% the esophagus lesions (EDs) and their P=0.05 fiducial I0086 A total of 200 male and female patients (100 per limits were calculated from the dose-response regression line. treatment group), 18 years of age or older, will be enrolled in The results obtained are provided in Table 1. this 8-week treatment, prospective, randomized, double

TABLE 1 Protective effects of dexloxiglumide, omeprazole and their combination treatment on acute reflux esophagitis in pylorus-ligated rats Treatment Average % Effect Group Doses (mg/kg) Score lesions vs. control EDso Control Saline 5.8 Dexloxiglumide 10 5.8 O 2O 4.8 17.2 37.5 mg/kg 40 2.6 51.7 60 2.2 62.1 100 O 100 Omeprazole O.1 S.6 3.4 O.3 5.8 O 5.4 mg/kg 1.O 4.8 14.3 3.0 2.7 53.4 Control Saline 5.9 Dexloxi + Omeprazole 10 - O.3 3.8 35.6 (CR2017 + 0.3 mg/kg 10 + 1.0 3.0 49.2 Omeprazole) = 20 + O.3 2.1 64.4 14.4 mg/kg 20 + 1.0 1.2 79.7 40+ 0.3 1.2 79.7 (CR2017 + 1.0 mg/kg 40 + 1.0 O 100 Omeprazole) = 9.8 mg/kg

0082. The calculated protective effects of Dexloxiglumide blind, placebo-controlled, parallel group study. To partici and Omeprazole administered separately were 37.5 mg/kg pate, patients must have received an adequate dose of a PPI and 5.4 mg/kg, respectively. The combination treatment of for 24 weeks during the previous 12 months without the two compounds produced an increase of protective effect. adequate relief of dyspeptic symptoms and have no endo The calculated EDso for the combination treatment were 14.4 scopic evidence of esophageal or gastric mucosal pathology mg/kg for dexloxiglumide plus omeprazole (0.3 mg/kg) and on esophagogastroduodenoscopy (EGD) and must have FD 9.8 mg/kg for dexloxiglumide plus omeprazole (1 mg/kg), symptoms (pain/discomfort centered in the upper abdomen, respectively. early satiety, fullness, bloating in the upper abdomen, nausea, 0083. On average the combination treatment produced a Vomiting or retching and belching or burping) present for >6 synergistic increase in efficacy for both examined drugs. For months. Upon entry into the run-in period, all patients will example, the combination treatment of 20 mg/kg dexloxiglu have their acid-suppression therapy standardized to esome mide plus 1 mg/kg omeprazole produced an 80% protective prazole 40 mg PO once daily (q.d.) and will continue on this effect versus a 32% expected, this latter being the sum of the regimen throughout the 4- to 6-week run-in and 8-week results obtained with the equivalent separate experiments, double-blind treatment periods. i.e., 17.2 and 14.3% of protective effect. I0087 Patients will first enter a 4- to 6-week, run-in period, during which they will use an electronic diary to report the Clinical Studies frequency and severity of their dyspeptic symptoms as well as Safety and Efficacy of Dexloxiglumide in the Relief of Dys heartburn, regurgitation, nighttime heartburn and nighttime peptic Symptoms regurgitation. In order to assure that dyspeptic/FD symptoms predominate overheartburn symptoms (if present despite PPI 0084. To assess the safety and efficacy of dexloxiglumide treatment) heartburn and acid regurgitation will also be in the relief of dyspeptic symptoms, we propose to conduct a assessed daily during the two-week run-in period. Delinea placebo-controlled, double-blind study in male and female tion of the patient's occasional heartburn symptoms at base patients who have a documented history of functional dys line will also allow assessment of the potential efficacy of US 2011/0065797 A1 Mar. 17, 2011

dexloxiglumide for the relief of these symptoms remaining siderable modification, alteration, and equivalents in form despite adequate PPI therapy. To be eligible for randomiza and function, as will be apparent to those of ordinary skill in tion, patients reporting heartburn and regurgitation during the the pertinent art having the benefit of this disclosure. Conse run-in period must demonstrate that their heartburn and quently, the invention is intended to be limited only by the regurgitation are of lesser severity and frequency than their spirit and scope of the appended claims, giving full cogni dyspeptic symptoms. Zance to equivalence in all respects. All references cited 0088 At the end of the run-in period, patients meeting herein are hereby incorporated by reference in their entirety. pre-specified dyspeptic symptom frequency and severity cri 1-18. (canceled) teria (i.e., at least two dyspeptic symptoms rated “relevant’ or 19. A pharmaceutical composition for treatment of a gas “severe” for at least two days of each week) will be random trointestinal disorder wherein the gastrointestinal disorder is ized 1:1 to receive dexloxiglumide for 8 weeks at a dose of selected from the group consisting of functional dyspepsia 300 mg b.i.d. or placebo. Thus, the safety and efficacy of and gastroesophageal reflux disease, and wherein the compo dexloxiglumide in the relief of dyspeptic symptoms and, sition comprises: (i) dexloxiglumide; (ii) a proton pump more particularly, functional dyspepsia (FD) will be evalu inhibitor (PPI); and (iii) a pharmaceutically acceptable carrier ated. or excipient, wherein the dexloxiglumide is present at a dos I0089. While the invention has been depicted and described age from 100 to 1000 mg and the proton pump inhibitor is with reference to exemplary embodiments, such reference present at a dosage of from 5 to 40 mg. does not imply a limitation on the invention, and no Such limitation is to be inferred. The invention is capable of con c c c c c