Prodrugs of metopimazine
Provided herein are methods, compounds, compositions, and kits for the treatment of an enteric nervous system disorder. Such methods may comprise administering to a subject an effective amount of a phenothiazine compound, a peripherally restricted dopamine decarboxylase inhibitor, and/or a peripherally restricted dopamine D2 receptor antagonist that does not substantially inhibit hERG channels.
1. A compound of Formula V:
or a salt thereof, wherein:
X′ is O or NH;
R 5 is C 5 -C 10 alkyl, C 1 -C 10 alkenyl, C 1 -C 10 alkynyl, C 4 -C 7 cycloalkyl, C 3 -C 7 heterocycloalkyl, C 6 -C 10 aryl, or C 6 -C 10 heteroaryl each of which may be unsubstituted or substituted with one or more R 6 groups;
each R 6 is independently —OR 7 , —SR 7 , —NR 7 R 8 , —COOR 7 , —CONR 7 R 8 , —OCOR 7 , —NR 7 —CO—R 8 , C 1 -C 10 alkyl, C 1 -C 10 alkenyl, C 1 -C 10 alkynyl, C 4 -C 7 cycloalkyl, C 3 -C 7 heterocycloalkyl, C 6 -C 10 aryl, or C 6 -C 10 heteroaryl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl may be unsubstituted or substituted with one or more —OR 7 , —SR 7 , —NR 7 R 8 , —COOR 7 , —CONR 7 R 8 , —OCOR 7 , or —NR 7 —CO—R 8 groups; and
each of R 7 and R 8 is independently H, C 1 -C 10 alkyl, C 1 -C 10 alkenyl, C 1 -C 10 alkynyl, C 4 -C 7 cycloalkyl, C 3 -C 7 heterocycloalkyl, C 6 -C 10 aryl, or C 6 -C 10 heteroaryl.
2. The compound of claim 1 or a salt thereof, wherein R 5 is C 1 -C 10 alkyl which is unsubstituted or substituted with one or more R 6 groups.
3. The compound of claim 2 or a salt thereof, wherein R 5 is substituted with one or more R 6 groups selected from —NR 7 R 8 , —COOR 7 , —CONR 7 R 8 , —OCOR 7 , and —NR 7 —CO—R 8 .
4. The compound of claim 3 or a salt thereof, wherein R 5 is substituted with one R 6 group selected from —NR 7 R 8 , —CONR 7 R 8 , and —NR 7 —CO—R 8 .
5. The compound of claim 3 or a salt thereof, wherein R 7 and R 8 are independently selected from H and C 1 -C 10 alkyl.
6. The compound of claim 1 or a salt thereof, wherein R 5 is unsubstituted C 5 -C 10 alkyl, C 1 -C 10 alkenyl, or C 1 -C 10 alkynyl.
7. The compound of claim 1 or a salt thereof, represented by Formula VI:
wherein:
X is O or NH;
R 9 is C 1 -C 6 linear or branched alkyl, benzyl, CH 2 OH, CH 2 CH 2 OH, or CH 2 CH 2 SMe;
Y and Z are both hydrogen or together can be a carbonyl oxygen;
R 10 is OH, OR 11 , or NR 12 R 13 ; and
R 11 , R 12 , and R 13 are C 1 -C 4 linear or branched alkyl.
8. A compound of Formula VII:
or a salt thereof, wherein:
X is O or NH;
R 14 is C 1 -C 4 linear or branched alkyl; and
R 15 is C 1 -C 6 linear or branched alkyl, phenyl, or C 4 -C 7 cycloalkyl.
9. A compound of Formula XI, or a salt thereof:
10. The compound of claim 8 or a salt thereof, represented by Formula XII:
11. A pharmaceutical composition comprising:
a) a compound of claim 1 ; and
b) a pharmaceutically acceptable carrier.
12. The pharmaceutical composition of claim 11 , wherein the pharmaceutical composition is formulated as an oral dosage form.
13. The pharmaceutical composition of claim 11 , wherein the pharmaceutical composition is formulated for transdermal delivery.
14. The pharmaceutical composition of claim 11 , wherein the pharmaceutical composition is formulated as a sublingual dosage form.
15. A compound of Formula V:
or a salt thereof, wherein:
X′ is O or NH;
R 5 is C 1 -C 10 alkyl substituted with one R 6 group selected from —NR 7 R 8 , —CONR 7 R 8 , and —NR 7 —CO—R 8 ; and
each of R 7 and R 8 is independently H, C 1 -C 10 alkyl, C 1 -C 10 alkenyl, C 1 -C 10 alkynyl, C 4 -C 7 cycloalkyl, C 3 -C 7 heterocycloalkyl, C 6 -C 10 aryl, or C 6 -C 10 heteroaryl.
16. The compound of claim 15 or a salt thereof, wherein R 7 and R 8 are independently selected from H and C 1 -C 10 alkyl.
17. A compound of Formula V:
or a salt thereof, wherein:
X′ is O; and
R 5 is unsubstituted C 2 -C 10 alkyl, C 1 -C 10 alkenyl, or C 1 -C 10 alkynyl.
18. The compound of claim 17 or a salt thereof, represented by Formula VIII:
19. The compound of claim 15 or a salt thereof, represented by Formula IX:
20. The compound of claim 15 or a salt thereof, represented by Formula X: