US2023219901A1PendingUtilityA1
Pegylated prodrugs of phenolic trpv1 agonists
Est. expiryJul 27, 2038(~12 yrs left)· nominal 20-yr term from priority
C07D 241/04A61P 25/04A61K 31/4965A61P 29/00C07D 493/08
80
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Claims
Abstract
Described herein are compounds, pharmaceutical compositions and medicaments that include such compounds, and methods of using such compounds to modulate transient receptor potential vanilloid 1 receptor (TRPV1) activity.
Claims
exact text as granted — not AI-modifiedWhat is claimed is:
1 . A compound having the structure of Formula (I):
wherein:
Y is a phenolic TRPV1 agonist, wherein the hydrogen atom of the phenolic hydroxyl group is replaced by a covalent bond to
R 1 is hydrogen or C 1 -C 6 alkyl;
R 2 is —(CH 2 CH 2 O) n R 3 , —C(O)(CH 2 ) m O(CH 2 CH 2 O) n R 3 , —C(O)O(CH 2 CH 2 O) n R 3 , —C(O)N(R 4 )(CH 2 CH 2 O) n R 3 , —C(O)R 5 , —C(O)OR 5 , or —C(O)N(R 4 )(R 5 );
R 3 is hydrogen or C 1 -C 6 alkyl;
R 4 is hydrogen or C 1 -C 6 alkyl;
R 5 is C 1 -C 50 alkyl;
m is 1-10;
n is 1-50; and
p is 1-9;
or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or hydrate thereof.
2 . The compound of claim 1 , wherein R 2 is —(CH 2 CH 2 O) n R 3 , —C(O)(CH 2 ) m O(CH 2 CH 2 O) n R 3 , —C(O)O(CH 2 CH 2 O) n R 3 , or —C(O)N(R 4 )(CH 2 CH 2 O) n R 3 .
3 . The compound of claim 1 or claim 2 , wherein R 2 is —C(O)(CH 2 ) m O(CH 2 CH 2 O) n R 3 .
4 . The compound of any one of claims 1-3 , wherein m is 1-5.
5 . The compound of any one of claims 1-4 , wherein m is 2.
6 . The compound of claim 1 or claim 2 , wherein R 2 is —(CH 2 CH 2 O) n R 3 .
7 . The compound of claim 1 or claim 2 , wherein R 2 is —C(O)O(CH 2 CH 2 O) n R 3 .
8 . The compound of claim 1 or claim 2 , wherein R 2 is —C(O)N(R 4 )(CH 2 CH 2 O) n R 3 .
9 . The compound of claim 8 , wherein R 4 is hydrogen.
10 . The compound of claim 8 , wherein R 4 is C 1 -C 6 alkyl.
11 . The compound of any one of claims 1-10 , wherein R 3 is hydrogen.
12 . The compound of any one of claims 1-10 , wherein R 3 is C 1 -C 6 alkyl.
13 . The compound of claim 12 , wherein R 3 is -CH 3 .
14 . The compound of any one of claims 1-13 , wherein n is 1-30.
15 . The compound of any one of claims 1-14 , wherein n is 2-20.
16 . The compound of any one of claims 1-15 , wherein n is 2-12.
17 . The compound of any one of claims 1-16 , wherein n is 4-10.
18 . The compound of claim 1 , wherein R 2 is —C(O)R 5 .
19 . The compound of claim 1 , wherein R 2 is —C(O)OR 5 .
20 . The compound of claim 1 , wherein R 2 is —C(O)N(R 4 )(R 5 ).
21 . The compound of any one of claims 18-20 , wherein R 5 is C 1 -C 25 alkyl.
22 . The compound of any one of claims 18-21 , wherein R 5 is C 1 -C 10 alkyl.
23 . The compound of any one of claims 18-22 , wherein R 5 is C 1 -C 5 alkyl.
24 . The compound of claim 23 , wherein R 5 is —CH 3 .
25 . The compound of any one of claims 1-24 , wherein R 1 is C 1 -C 6 alkyl.
26 . The compound of any one of claims 1-25 , wherein R 1 is C 1 -C 3 alkyl.
27 . The compound of any one of claims 1-26 , wherein R 1 is —CH 3 .
28 . The compound of any one of claims 1-26 , wherein R 1 is —CH 2 CH 3 .
29 . The compound of any one of claims 1-24 , wherein R 1 is hydrogen.
30 . The compound of any one of claims 1-29 , wherein p is 1.
31 . The compound of any one of claims 1-29 , wherein p is 2.
32 . The compound of any one of claims 1-31 , wherein Y is
R 6 is independently selected from hydrogen, halogen, —CN, —NH 2 , —NH(CH 3 ), —N(CH 3 ) 2 , —OH, —CO 2 H, -C(O)OC 1 -C 6 alkyl, —C(O)NH 2 , -C(O)NH(C 1 -C 6 alkyl), -C(O)N(C 1 -C 6 alkyl) 2 , —SO 2 NH 2 , -SO 2 NH(C 1 -C 6 alkyl), -SO 2 N(C 1 -C 6 alkyl) 2 , C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, C 1 -C 6 fluoroalkyl, C 1 -C 6 heteroalkyl, C 1 -C 6 alkoxy, C 1 -C 6 fluoroalkoxy, C 2 -C 9 heterocycloalkyl, C 6 -C 10 aryl, C 1 -C 9 heteroaryl, C 6 -C 10 aryloxy, C 1 -C 6 alkylthio, C 6 -C 10 arylthio, C 1 -C 6 alkylsulfoxide, C 6 -C 10 arylsulfoxide, C 1 -C 6 alkylsulfone, and C 6 -C 10 arylsulfone; J is —NHC(O)R 7 or —C(O)OR 7 ; and R 7 is C 1 -C 12 alkyl optionally substituted with one or more groups selected from halogen, —CN, —NH 2 , —NH(CH 3 ), —N(CH 3 ) 2 , —OH, —CO 2 H, -C(O)OC 1 -C 6 alkyl, —C(O)NH 2 , -C(O)NH(C 1 -C 6 alkyl), -C(O)N(C 1 -C 6 alkyl) 2 , —SO 2 NH 2 , -SO 2 NH(C 1 -C 6 alkyl), -SO 2 N(C 1 -C 6 alkyl) 2 , C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, C 1 -C 6 fluoroalkyl, C 1 -C 6 heteroalkyl, C 1 -C 6 alkoxy, C 1 -C 6 fluoroalkoxy, C 2 -C 9 heterocycloalkyl, C 6 -C 10 aryl, C 1 -C 9 heteroaryl, C 6 -C 10 aryloxy, C 1 -C 6 alkylthio, C 6 -C 10 arylthio, C 1 -C 6 alkylsulfoxide, C 6 -C 10 arylsulfoxide, C 1 -C 6 alkylsulfone, and C 6 -C 10 arylsulfone.
33 . The compound of claim 32 , wherein J is —NHC(O)R 7 .
34 . The compound of claim 32 , wherein J is —C(O)OR 7 .
35 . The compound of any one of claims 32-34 , wherein R 7 is unsubstituted C 1 -C 12 alkyl.
36 . The compound of any one of claims 32-35 , wherein R 6 is C 1 -C 6 alkoxy.
37 . The compound of any one of claims 1-31 , wherein Y is
.
38 . The compound of claim 37 , wherein Y is
.
39 . A compound, or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or hydrate thereof, having the structure:
.
40 . A compound, or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or hydrate thereof, having the structure:
.
41 . A pharmaceutical composition comprising a compound, or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or hydrate thereof, as claimed in any one of claims 1-40 , and a pharmaceutically acceptable diluent, excipient or binder.
42 . A method of treating pain in a subject, comprising administering to the subject a therapeutically effective amount of a compound of any one of claims 1-40 , or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or hydrate thereof.
43 . The method of claim 42 , wherein the pain is associated with cancer.Cited by (0)
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