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(12) Patent Application Publication (10) Pub. No.: US 2017/0143734 A1 DE COLLE Et Al

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(12) Patent Application Publication (10) Pub. No.: US 2017/0143734 A1 DE COLLE Et Al US 20170143734A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2017/0143734 A1 DE COLLE et al. (43) Pub. Date: May 25, 2017 (54) PRODRUGS OF METOPMAZINE Publication Classification (51) Int. Cl. (71) Applicant: Neurogastrx, Inc., Campbell, CA (US) A6II 3/545 (2006.01) A6IR 9/00 (2006.01) (72) Inventors: Cyril DE COLLE, Campbell, CA A 6LX 9/70 (2006.01) (US); Pankaj PASRICHA, Ellicott C07D 417/06 (2006.01) City, MD (US); David WUSTROW, A63L/98 (2006.01) Los Gatos, CA (US) (52) U.S. Cl. (21) Appl. No.: 15/320,724 CPC ........ A6IK3I/5415 (2013.01); C07D 417/06 (2013.01); A61K 31/198 (2013.01); A61 K (22) PCT Fed: Jun. 23, 2015 9/7023 (2013.01); A61K 9/006 (2013.01) (86) PCT No.: PCT/US 15/37258 (57) ABSTRACT S 371 (c)(1), Provided herein are methods, compounds, compositions, and kits for the treatment of an enteric nervous system (2) Date: Dec. 20, 2016 disorder. Such methods may comprise administering to a Subject an effective amount of a phenothiazine compound, a peripherally restricted dopamine decarboxylase inhibitor, Related U.S. Application Data and/or a peripherally restricted dopamine D2 receptor (60) Provisional application No. 62/016.235, filed on Jun. antagonist that does not substantially inhibit hERG chan 24, 2014. nels. Patent Application Publication May 25, 2017. Sheet 1 of 2 US 2017/O143734 A1 Repeated measures one-way ANOVA data 2 5 2 O 1 5 1 O FIGURE 1 Patent Application Publication May 25, 2017. Sheet 2 of 2 US 2017/O143734 A1 Solid Gastric Emptying (%) QCcodoG |- ODCON,COLO<!--(NI<- G2Cco ||||||| IIIIII FIGURE 2 US 2017/O 143734 A1 May 25, 2017 PRODRUGS OF METOPMAZINE The safety concerns relate to (1) unwanted cardiac side effects caused by, e.g., interaction of the agents with ion CROSS-REFERENCE channels involved in cardiac action potentials, and (2) unwanted motor dysfunction caused by the actions of the 0001. This application claims priority to U.S. Provisional dopamine antagonists which cross the blood brain barrier Patent application Ser. No. 62/016,235, filed Jun. 24, 2014, into the brain. For example, it has been established that which is hereby incorporated by reference in its entirety. many dopamine receptor antagonists inhibit hERG channels (a type of potassium channel) which can cause drug-induced BACKGROUND long QT syndrome, a heart condition characterized by 0002 The enteric nervous system (ENS) comprises about abnormal cardiac action potential rhythms. Long QT syn one hundred million neurons embedded in the lining of the drome can increase risk of cardiac arrhythmias, which may gastrointestinal system. The ENS innervates the gastroin lead to sudden cardiac death. Indeed, the dopamine D2 testinal system, including the esophagus, the stomach (e.g., antagonist domperidone has been shown to inhibit hERG gastric area), and the intestines. Motor neurons of the ENS activity and increase risk of long QT syndrome, and increase control stomach muscle contractility, peristalsis, and churn risk of Sudden cardiac death. This has resulted in an FDA ing of intestinal contents. It has been estimated that about ban on the use of domperidone in the United States and an 50% of the body’s dopamine is found in the ENS. initiated review of the safety of domperidone use by the 0003 Gastrointestinal (GI) tract disorders affect many European Medicines Agency. Metoclopramide cannot be people. Irritable bowel syndrome (IBS), a disorder in which taken for more than 12 weeks and has a black box warning the intestine functions abnormally due to dysfunction of the for CNS-related side effects such as tardive dyskinesia, a muscles or nerves of the GI tract, affects 10% to 15% of the difficult-to-treat and often incurable disorder characterized adult population. Symptoms of IBS include constipation, by involuntary, repetitive body movements. diarrhea, and abdominal pain. Functional dyspepsia (dys pepsia caused by a dysfunction of the muscles or nerves SUMMARY associated with the upper GI tract) affects 10% to 20% of the 0007 Aspects of the present disclosure relate to methods adult population. Gastroparesis, a disorder causing inad of treating disorders, e.g., functional and motility disorders equate grinding of food by the stomach and delayed gastric of the gastrointestinal (GI) tract. Such methods may com emptying, affects up to 10% of the general population. prise, e.g., modulating the enteric nervous system (ENS). Gastroesophageal reflux disorder (GERD), a chronic diges For example, described herein is a method of treating tive disease that occurs when stomach acid and/or bile backs functional and motility disorders of the GI tract by admin up into the esophagus, has been estimated to affect up to istrating an effective amount of a peripherally-restricted 35% of infants in the first few months of life. dopamine receptor D2 antagonist that does not have adverse 0004. In addition, gastrointestinal disorders can be asso cardiac effects on an individual and modulating the enteric ciated with a number of other diseases. For example, some nervous system (ENS). of the earliest symptoms of Parkinson's disease, a disorder 0008. The present disclosure also provides for a method characterized by neurodegeneration of dopamine neurons, of treating gastroparesis by administering an effective include, e.g., constipation and other gastrointestinal Symp amount of a composition of metopimazine, metopimazine toms, likely due to degeneration or dysfunction of ENS acid, or a prodrug thereof, modulating the ENS, and treating dopamine neurons. As another example, diabetes is one of gastroparesis. the most common causes of gastroparesis, as chronic high 0009. The present disclosure also provides for a method blood Sugar can damage the vagus nerve which modulates of treating vomiting and nausea associated with a GI tract the enteric nervous system. Multiple sclerosis is another disorder, by administering an effective amount of a periph disease that is associated with ENS disorders such as, e.g., erally-restricted dopamine receptor D2 antagonist that does gastroparesis. Migraine headaches are commonly associated not have adverse cardiac effects on an individual, and with gastric stasis. Chemotherapy-induced nausea and/or modulating the ENS. vomiting have been estimated to affect 85% of cancer 0010. The present disclosure provides for a method of patients undergoing chemotherapy and can result in discon improving gastric emptying, by administering an effective tinuation of treatment. If the chemotherapy-induced nausea amount of a peripherally-restricted dopamine receptor D2 and/or vomiting are not properly managed, it can cause antagonist that does not have adverse cardiac effects on an dehydration and poor quality of life and may result in individual, and modulating the ENS. discontinuation of chemotherapy. 0011. The present disclosure further provides for a 0005. ENS dysfunction has been implicated in several of method of improving gastric emptying, by administering an the disorders described above. For example, impaired or effective amount of carbidopa, and modulating the ENS. dysfunctional ENS neuronal signaling has been strongly 0012. The present invention provides a method of treat implicated as a causative factor for gastroparesis. ing functional and motility disorders of the GI tract, includ 0006. There are currently no adequate treatments for ing the steps of administrating an effective amount of a these disorders. For example, IBS treatments lubiprostone compound, which is a peripherally-restricted dopamine and linaclotide are used to mimic infectious diarrhea in order receptor D2 antagonist that does not have adverse cardiac to treat constipation; however, these agents do not correct effects on an individual; and modulating the enteric nervous the underlying ENS dysfunction and are marginally effec system (ENS). In some embodiments, the GI tract disorder tive. The dopamine D2 receptor antagonists domperidone is chosen from the group consisting of IBS/abdominal pain, and metoclopramide have been previously indicated for the functional dyspepsia, gastroparesis, cyclic vomiting Syn treatment of nausea and vomiting, however, their use is drome, chemotherapy-induced nausea and vomiting. The discouraged due to significant safety issues. Two significant disclosure also provides a method of treating gastroparesis, US 2017/O 143734 A1 May 25, 2017 including the steps of administering an effective amount of embodiments, the dopamine decarboxylase inhibitor does a compound chosen from the group consisting of metopi not cross the blood-brain barrier of the subject. In some mazine, metopimazine acid, and a prodrug thereof modu embodiments, the dopamine decarboxylase inhibitor is car lating the enteric nervous system (ENS); and treating gas bidopa. In some embodiments, the dopamine decarboxylase troparesis. inhibitor is selected from the group consisting of benseraz 0013 The disclosure also provides a method of treating ide, methyldopa, or C-difluoromethyl-dopa (DFMD, DFM Vomiting and nausea associated with a GI tract disorder, DOPA). including the steps of administering an effective amount of 0021. The disclosure also provides a method of treating a peripherally-restricted dopamine receptor D2 antagonist an enteric nervous system disorder in a human Subject in that does not have adverse cardiac effects on an individual; need thereof, comprising administering to the Subject a and modulating the enteric nervous system (ENS). compound that is a peripherally restricted dopamine D2 0014. The disclosure also provides a method
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