Capsaicinoid prodrug compounds and their use in treating medical conditions
The invention provides capsaicinoid prodrug compounds, pharmaceutical compositions, and their use in the treatment of medical conditions, such as pain, and in agonizing TRPV1 activity.
1. A compound represented by Formula III:
or a pharmaceutically acceptable salt thereof; wherein:
X is —C(R 1 ) 2 — or —O—;
Y is —C(R 2 ) 2 — or a bond;
R 1 represents independently for each occurrence hydrogen, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, C 6 aryl, or 3-8 membered heterocycloalkyl; or two occurrences of R 1 are taken together with the carbon atom to which they are attached to form a 3-6 membered saturated carbocyclic or heterocyclic ring;
R 2 represents independently for each occurrence hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, C 6 aryl, or 3-8 membered heterocycloalkyl; or two occurrences of R 2 are taken together to represent an oxo group; or two occurrences of R 2 are taken together with the carbon atom to which they are attached to form a 3-6 membered saturated carbocyclic or heterocyclic ring;
R 3 is hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, 4-8 membered heterocycloalkyl, or —C(═NH)—NH 2 ; wherein C 1-6 alkyl, C 3-7 cycloalkyl, and 4-8 membered heterocycloalkyl are each optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, hydroxyl, oxo, C 1-4 alkyl, C 1-4 haloalkyl, C 3-7 cycloalkyl, and C 1-4 alkoxyl;
R 4 is hydrogen, or two occurrences of R 4 are taken together with the carbon atoms to which they are attached to form a cis or trans double bond; and
Ring A is one of the following:
a 6-membered carbocyclic aromatic ring optionally substituted with 1, 2, or 3 substitutents independently selected from the group consisting of halogen, hydroxyl, C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, C 1-4 alkoxyl, and C 1-4 haloalkoxyl; or
a C 3-8 saturated or partially unsaturated carbocyclic ring optionally substituted with 1, 2, or 3 substitutents independently selected from the group consisting of halogen, hydroxyl, oxo, C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, C 1-4 alkoxyl, and C 1-4 haloalkoxyl.
2. A compound of Formula IV or V, wherein Formula IV is represented by:
or a pharmaceutically acceptable salt thereof; wherein:
R 1 is hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, C 6 aryl, or 4-8 membered heterocycloalkyl; or R 1 and an occurrence of R 2A are taken together with the atoms to which they are attached to form a 3-8 membered saturated heterocyclic ring optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, hydroxyl, oxo, C 1-4 alkyl, C 1-4 haloalkyl, C 3-7 cycloalkyl, and C 1-4 alkoxyl;
R 2A represents independently for each occurrence hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, C 6 aryl, or 3-8 membered heterocyclyl; or two occurrences of R 2A are taken together to represent an oxo group; or two occurrences of R 2A are taken together with the carbon atom to which they are attached to form a 3-6 membered saturated carbocyclic or heterocyclic ring; or an occurrence of R 2A and an occurrence of R 2B are taken together with the carbon atoms to which they are attached to form a 3-6 membered saturated carbocyclic or heterocyclic ring;
R 2B represents independently for each occurrence hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, C 6 aryl, or 3-8 membered heterocyclyl; or two occurrences of R 2B are taken together to represent an oxo group; or two occurrences of R 2B are taken together with the carbon atom to which they are attached to form a 3-6 membered saturated carbocyclic or heterocyclic ring;
R 3 is hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, 4-8 membered heterocycloalkyl, or —C(═NH)—NH 2 ; wherein C 1-6 alkyl, C 3-7 cycloalkyl, and 4-8 membered heterocycloalkyl are each optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, hydroxyl, oxo, C 1-4 alkyl, C 1-4 haloalkyl, C 3-7 cycloalkyl, and C 1-4 alkoxyl; and
R 4 is hydrogen, or two occurrences of R 4 are taken together with the carbon atoms to which they are attached to form a cis or trans double bond; and
Formula V is represented by:
or a pharmaceutically acceptable salt thereof; wherein:
R 1 is hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, C 6 aryl, or 4-8 membered heterocycloalkyl; or R 1 and an occurrence of R 2A are taken together with the atoms to which they are attached to form a 3-8 membered saturated heterocyclic ring optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, hydroxyl, oxo, C 1-4 alkyl, C 1-4 haloalkyl, C 3-7 cycloalkyl, and C 1-4 alkoxyl;
R 2A represents independently for each occurrence hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, C 6 aryl, or 3-8 membered heterocyclyl; or two occurrences of R 2A are taken together to represent an oxo group; or two occurrences of R 2A are taken together with the carbon atom to which they are attached to form a 3-6 membered saturated carbocyclic or heterocyclic ring; or an occurrence of R 2A and an occurrence of R 2B are taken together with the carbon atoms to which they are attached to form a 3-6 membered saturated carbocyclic or heterocyclic ring;
R 2B represents independently for each occurrence hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, C 6 aryl, or 3-8 membered heterocyclyl; or two occurrences of R 2B are taken together to represent an oxo group; or two occurrences of R 2B are taken together with the carbon atom to which they are attached to form a 3-6 membered saturated carbocyclic or heterocyclic ring;
R 3 is hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, 4-8 membered heterocycloalkyl, or —C(═NH)—NH 2 ; wherein C 1-6 alkyl, C 3-7 cycloalkyl, and 4-8 membered heterocycloalkyl are each optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, hydroxyl, oxo, C 1-4 alkyl, C 1-4 haloalkyl, C 3-7 cycloalkyl, and C 1-4 alkoxyl;
R 4 is hydrogen, or two occurrences of R 4 are taken together with the carbon atoms to which they are attached to form a cis or trans double bond; and
R 5 is hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, C 6 aryl, or 3-8 membered heterocyclyl.
3. A pharmaceutical composition comprising a compound of claim 2 and a pharmaceutically acceptable carrier.
4. A method of treating or preventing pain in a subject, comprising administering a therapeutically effective amount of a compound of claim 2 to a subject in need thereof to treat or prevent the pain.
5. A method of agonizing the activity of TRPV1, comprising exposing a TRPV1 to an effective amount of a compound of claim 2 to agonize the activity of said TRPV1.
6. The compound of claim 2 , wherein the compound is a compound of Formula IV or a pharmaceutically acceptable salt thereof.
7. The compound of claim 6 , wherein R 1 is hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, C 6 aryl, or 4-8 membered heterocycloalkyl.
8. The compound of claim 6 , wherein R 2A represents independently for each occurrence hydrogen, C 1-4 alkyl, or C 1-4 haloalkyl.
9. The compound of claim 6 , wherein an occurrence of R 2A and an occurrence of R 2B are taken together with the carbon atoms to which they are attached to form a 3-6 membered saturated carbocyclic or heterocyclic ring.
10. The compound of claim 6 , wherein R 2B represents independently for each occurrence hydrogen, C 1-4 alkyl, or C 1-4 haloalkyl.
11. The compound of claim 6 , wherein R 3 is hydrogen, or R 3 is C 1-6 alkyl, C 1-6 haloalkyl, or C 3-7 cycloalkyl.
12. The compound of claim 2 , wherein the compound is a compound of Formula V or a pharmaceutically acceptable salt thereof.
13. The compound of claim 12 , wherein R 1 is hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, C 6 aryl, or 4-8 membered heterocycloalkyl.
14. The compound of claim 12 , wherein R 2A represents independently for each occurrence hydrogen, C 1-4 alkyl, or C 1-4 haloalkyl.
15. The compound of claim 12 , wherein an occurrence of R 2A and an occurrence of R 2B are taken together with the carbon atoms to which they are attached to form a 3-6 membered saturated carbocyclic or heterocyclic ring.
16. The compound of claim 12 , wherein R 2B represents independently for each occurrence hydrogen, C 1-4 alkyl, or C 1-4 haloalkyl.
17. The compound of claim 12 , wherein R 3 is hydrogen, or R 3 is C 1-6 alkyl, C 1-6 haloalkyl, or C 3-7 cycloalkyl.
18. The compound of claim 12 , wherein R 5 is C 1-6 alkyl, C 1-6 haloalkyl, or C 3-7 cycloalkyl.
19. The compound of claim 2 , wherein the compound is a compound in the following Table 2 or 2A, or a pharmaceutically acceptable salt thereof:
TABLE 2
No.
R*
II-1
II-2
II-3
II-4
II-5
II-6
II-7
II-8
II-9
II-10
II-11
II-12
II-13
II-14
II-15
II-16
II-17
II-18
II-19
II-20
II-21
II-22
II-23
II-24
II-25
II-26
II-27
II-28
II-29
II-30
II-31
II-32
II-33
II-34
II-35
II-36
II-37
II-38
II-39
II-40
II-41
II-42
TABLE 2A
No.
R*
II-1
II-2
II-3
II-4
II-5
II-6
II-7
II-8
II-9
II-10
II-11
II-12
II-13
II-14
II-15
II-16
II-17
II-18
II-19
II-20
II-21
II-22
II-23
II-24
II-25
II-26
II-27
II-28
II-29
II-30
II-31
II-32
II-33
II-34
II-35
II-36
II-37
II-38
II-39
II-40
II-41
II-42
.
20. A compound in the following Table 5 or 5A, or a pharmaceutically acceptable salt thereof:
TABLE 5
No.
R*
V-1
V-2
V-3
V-4
V-5
V-6
V-7
V-8
V-9
V-10
V-11
V-12
V-13
V-14
V-15
V-16
V-17
V-18
V-19
V-20
V-21
V-22
V-23
V-24
V-25
V-26
V-27
V-28
V-29
V-30
TABLE 5A
No.
R*
V-1
V-2
V-3
V-4
V-5
V-6
V-7
V-8
V-9
V-10
V-11
V-12
V-13
V-14
V-15
V-16
V-17
V-18
V-19
V-20
V-21
V-22
V-23
V-24
V-25
V-26
V-27
V-28
V-29
V-30