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 13. The compound of claim 1 or a salt thereof, represented by Formula XII: N \,z' (XII) OC O N O 1. O S O-1 10. The compound of claim 1 or a salt thereof, represented by Formula IX: N \2

(IX) O CCCS

O O. 14. A pharmaceutical composition comprising: a) a compound of claim 1; and N r b) a pharmaceutically acceptable carrier. -NN 15. The pharmaceutical composition of claim 14, wherein O O the pharmaceutical composition is formulated as an oral N N^ dosage form. 16. The pharmaceutical composition of claim 15, wherein the oral dosage form is selected from the group consisting of a pill, tablet, capsule, granule, lozenge, pastille, and powder. OCCS 17. The pharmaceutical composition of claim 14, wherein the pharmaceutical composition is formulated for transder 11. The compound of claim 1 or a salt thereof, represented mal delivery. 18. (canceled) by Formula X: 19. The pharmaceutical composition of claim 14, wherein the pharmaceutical composition is formulated as a Sublin (X) gual dosage form. 20. (canceled) 21. (canceled) 22. (canceled) N r 23. (canceled) -NN. 24. (canceled) 25. (canceled) 26. (canceled) 27. (canceled) 28. (canceled) 29. (canceled) cro 30. (canceled) 31. (canceled) 32. (canceled) US 2017/O 143734 A1 May 25, 2017 43

33. (canceled) or a salt, thereof, wherein: 34. (canceled) X is O or NH; 35. (canceled) Rs is C-Co alkyl, C-Coalkenyl, C-Co alkynyl, C-C, cycloalkyl, C-C, heterocycloalkyl, Co-Co aryl, or 36. (canceled) Co-Co heteroaryl each of which may be unsubstituted 37. A kit, comprising: or Substituted with one or more R groups; a) at least one unit dosage of a pharmaceutical composi- each Re is independently —OR7, —SR-7, —NR7Rs. tion comprising a compound of Formula V: - COOR, CONRRs –OCOR - NR, CO Rs. C-Clo alkyl, C-Clo alkenyl, C-Clio alkynyl, C-C cycloalkyl, C-C, heterocycloalkyl, Co-Co aryl, (V) or Co-Co heteroaryl, wherein the alkyl, alkenyl, alky O nyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl may be unsubstituted or substituted with one or more —OR7, SR 7, NR7Rs – COOR 7, —CONR,Rs. X-Rs —OCOR7, or —NR, CO-Rs groups; and N each of R, and Rs is independently H, C-C alkyl, C-Co alkenyl, C-C alkynyl, C-C cycloalkyl, C-C, heterocycloalkyl, Co-Co aryl, or Co-Co het eroaryl. ONa O b) instructions for treating an enteric nervous system N Sn disorder in a human Subject in need thereof. 38. The kit of claim 37, further comprising a dopamine decarboxylase inhibitor, wherein the dopamine decarboxy S lase inhibitor does not effectively cross a blood brain barrier of the human Subject. k k k k k