Kappa opioid agonists and uses thereof
View Patent ↗Provided are compounds of Formula I: and pharmaceutically acceptable salts and solvates thereof, wherein R 1 , R 2 , R 3 , R 4 , R 5 , and R 6 are as described herein. The compounds of Formula I are agonists of the kappa opioid receptor and relate to and/or have application(s) in (among others) the fields of drug discovery, pharmacotherapy, physiology, organic chemistry and polymer chemistry.
1. A compound according to Formula I:
wherein:
R 1 is an optionally substituted phenyl;
R 2 is hydrogen or phenyl;
R 3 is selected from hydrogen and an optionally substituted lower alkyl;
R 4 is a phenyl substituted with —X-POLY;
R 5 and R 6 together with the nitrogen to which they are attached form an optionally substituted pyrrolidinyl or azetidinyl ring;
X is an optional linker selected from a covalent bond; —C(O)NH—; —C(O)NHCH 2 —; —C(O)NHCH 2 CH 2 —; —OC(O)NH—; —C(O)NH—; —O—; —NHC(O)—; —NHC(O)CH 2 —; —NHC(O)CH 2 O—; —NHC(O)CH 2 CH 2 —; —NH—; or —NHS(O) 2 —; and
POLY is a poly(alkylene oxide) oligomer comprising 2 to 10 alkylene oxide monomers;
or pharmaceutically acceptable salts and solvates thereof.
2. The compound of claim 1 , wherein R 1 is substituted with 1, 2, or 3 halogen atoms.
3. The compound of claim 1 , wherein R 3 is methyl.
4. The compound of claim 1 , wherein R 5 and R 6 are taken together to form an optionally substituted pyrrolidinyl.
5. The compound claim 1 , wherein the poly(alkylene oxide) oligomer is a poly(ethylene oxide) oligomer.
6. The compound of claim 1 , wherein POLY is end-capped with a hydroxyl group, a lower alkoxy group, or a trifluoromethoxy group.
7. The compound of claim 1 according to the following formula:
wherein:
POLY is —(CH 2 CH 2 O) n —Y;
n is an integer from 2 to 10; and
Y is hydrogen, methyl, or trifluoromethoxy;
or pharmaceutically acceptable salts and solvates thereof.
8. The compound of claim 7 according to the following formula:
or pharmaceutically acceptable salts and solvates thereof.
9. The compound of claim 1 according to the following formula:
wherein:
POLY is —(CH 2 CH 2 O) n —Y;
n is an integer from 42 to 10; and
Y is hydrogen, methyl, or trifluoromethoxy;
or pharmaceutically acceptable salts and solvates thereof.
10. The compound of claim 9 according to the following formula:
or pharmaceutically acceptable salts and solvates thereof.
11. The compound of claim 1 according to any of the following formulas:
or pharmaceutically acceptable salts and solvates thereof.
12. A pharmaceutical composition comprising a compound of claim 1 and at least one pharmaceutically acceptable excipient.
13. A method of treating pain or inflammation comprising administering a compound of claim 1 to a patient in need thereof.