Kappa opioid agonists and uses thereof
Provided are compounds of Formula I; and pharmaceutically acceptable salts and solvates thereof: The compounds of Formula I described herein 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;
R 3 is selected from hydrogen and an optionally substituted alkyl;
R 4 is an optionally substituted phenyl;
R 5 and R 6 taken together with the nitrogen to which they are attached form a pyrrolidinyl or azetidinyl ring substituted with —X-POLY;
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 —; 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 to 3 halogens.
3. The compound of claim 1 , wherein R 3 is hydrogen.
4. The compound of claim 1 , wherein R 3 is methyl.
5. The compound of 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 , having a structure selected from:
wherein X is selected from —O—, —OC(O)NH—, and a covalent bond;
POLY is ˜(CH 2 CH 2 O) n —Y,
n is an integer from 2 to 10, and
Y is selected from hydrogen, methyl, or trifluoromethoxy
or pharmaceutically acceptable salts and solvates thereof.
8. The compound of claim 1 , having the structure:
wherein X is selected from —O—, —OC(O)NH—, and a covalent bond;
POLY is —(CH 2 CH 2 O) n —Y,
n is an integer from 2 to 10, and
Y is selected from hydrogen, methyl, or trifluoromethoxy
or pharmaceutically acceptable salts and solvates thereof.
9. A pharmaceutical composition comprising the compound of claim 1 and at least one pharmaceutically acceptable excipient.
10. A composition of matter comprising the compound of claim 1 , wherein the compound is present in a dosage form.
11. A method of treating pain or inflammation comprising administering the compound of claim 1 to a patient in need thereof.
12. A compound having the structure:
wherein R 10 is selected from the group consisting of ˜H, ˜OCH 2 CH 2 OH, ˜OCH 2 CH 2 OCH 3 , ˜NHCH 2 CH 2 OH, and ˜NHCH 2 CH 2 OCH 3 ,
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)—; and —NHC(O)CH 2 —;
POLY is a poly(alkylene oxide) oligomer comprising 2 to 10 alkylene oxide monomers, or pharmaceutically acceptable salts and solvates thereof.
13. The compound of claim 12 , wherein X-POLY is ˜O—(CH 2 CH 2 O) n —Y, wherein n is 2 to 30, and Y is selected from hydrogen, lower alkyl and trifluoromethoxy.
14. A compound having the following structure:
wherein:
n is an integer of from 1 to 30;
R 10 is selected from the group consisting of ˜H, ˜OCH 2 CH 2 OH, ˜OCH 2 CH 2 OCH 3 , ˜NHCH 2 CH 2 OH, and ˜NHCH 2 CH 2 OCH 3 ;
R 11 is selected from the group consisting of ˜H, ˜CH 3 , and ˜CF 3 , and pharmaceutically acceptable salts and solvates thereof.