Mu opioid receptor modulators

Patent metadata

Field	Value
Publication number	US-11484525-B2
Application number	US-202016921843-A
Country	US
Kind code	B2
Filing date	Jul 6, 2020
Priority date	Jul 9, 2015
Publication date	Nov 1, 2022
Grant date	Nov 1, 2022

Abstract

Described herein, inter alia, are compositions and methods for modulating mu opioid receptor activity.

First claim

What is claimed is:

1. A method of treating pain in a subject in need of said treatment, said method comprising administering to said subject an effective amount of a compound having the formula:

wherein:
W is O or S;
Ring A is independently an R 3 -substituted or unsubstituted phenyl or R 3 -substituted or unsubstituted pyridinyl;
Ring B is independently an R 4 -substituted or unsubstituted thienyl, R 4 -substituted or unsubstituted phenyl, R 4 -substituted or unsubstituted benzothienyl, R 4 -substituted or unsubstituted naphthyl, R 4 -substituted or unsubstituted benzofuranyl, R 4 -substituted or unsubstituted furanyl, R 4 -substituted or unsubstituted pyrrolyl-2,5-dione, or R 4 -substituted or unsubstituted 2,3-dihydro-1H-indenyl;
L 1 is independently a bond or unsubstituted (C 1 -C 5 ) alkylene;
L 2 is an unsubstituted (C 1 -C 5 ) alkylene;
R 1 and R 2 are independently hydrogen or substituted or unsubstituted (C 1 -C 5 ) alkyl;
R 3 is independently hydrogen, substituted or unsubstituted (C 1 -C 5 ) alkyl or substituted or unsubstituted 2 to 5 membered heteroalkyl;
R 4 is independently hydrogen, halogen, —CX 3 , —OR 14 , —CHX 2 , —CH 2 X, —OCX 3 , —OCHX 2 , oxo, substituted or unsubstituted (C 1 -C 5 ) alkyl or substituted or unsubstituted 2 to 5 membered heteroalkyl;
R 5 is hydrogen, —CF 3 , —CN, —COOH, —CONH 2 , —CHF 2 , —CH 2 F, substituted or unsubstituted (C 1 -C 5 ) alkyl, or substituted or unsubstituted 2 to 5 membered heteroalkyl;
R 6 is hydrogen, —CF 3 , —CN, —COOH, —CONH 2 , —CHF 2 , —CH 2 F, substituted or unsubstituted (C 1 -C 5 ) alkyl, or substituted or unsubstituted 2 to 5 membered heteroalkyl;
R 10 and R 14 are independently hydrogen;
X is —Cl, —Br, —I, or —F.

2. The method of claim 1 , wherein said method does not comprise an increased risk of respiratory depression or constipation.

3. A method of treating an opioid overdose or addiction in a subject in need of said treatment, said method comprising administering to said subject an effective amount of a compound having the formula:

wherein:
W is O or S;
Ring A is independently an R 3 -substituted or unsubstituted phenyl or R 3 -substituted or unsubstituted pyridinyl;
Ring B is independently an R 4 -substituted or unsubstituted thienyl, R 4 -substituted or unsubstituted phenyl, R 4 -substituted or unsubstituted benzothienyl, R 4 -substituted or unsubstituted naphthyl, R 4 -substituted or unsubstituted benzofuranyl, R 4 -substituted or unsubstituted furanyl, R 4 -substituted or unsubstituted pyrrolyl-2,5-dione, or R 4 -substituted or unsubstituted 2,3-dihydro-1H-indenyl;
L 1 is independently a bond or unsubstituted (C 1 -C 5 ) alkylene;
L 2 is an unsubstituted (C 1 -C 5 ) alkylene;
R 1 and R 2 are independently hydrogen or substituted or unsubstituted (C 1 -C 5 ) alkyl;
R 3 is independently hydrogen, substituted or unsubstituted (C 1 -C 5 ) alkyl or substituted or unsubstituted 2 to 5 membered heteroalkyl;
R 4 is independently hydrogen, halogen, —CX 3 , —OR 14 , —CHX 2 , —CH 2 X, —OCX 3 , —OCHX 2 , oxo, substituted or unsubstituted (C 1 -C 5 ) alkyl or substituted or unsubstituted 2 to 5 membered heteroalkyl;
R 5 is hydrogen, —CF 3 , —CN, —COOH, —CONH 2 , —CHF 2 , —CHF, substituted or unsubstituted (C 1 -C 5 ) alkyl, or substituted or unsubstituted 2 to 5 membered heteroalkyl;
R 6 is hydrogen, —CF 3 , —CN, —COOH, —CONH 2 , —CHF 2 , —CHF, substituted or unsubstituted (C 1 -C 5 ) alkyl, or substituted or unsubstituted 2 to 5 membered heteroalkyl;
R 10 and R 14 are independently hydrogen;
X is —Cl, —Br, —I, or —F.

4. A method of treating a psychiatric disorder in a subject in need of said treatment, said method comprising administering to said subject an effective amount of a compound having the formula:

wherein:
W is O or S;
Ring A is independently an R 3 -substituted or unsubstituted phenyl or R 3 -substituted or unsubstituted pyridinyl;
Ring B is independently an R 4 -substituted or unsubstituted thienyl, R 4 -substituted or unsubstituted phenyl, R 4 -substituted or unsubstituted benzothienyl, R 4 -substituted or unsubstituted naphthyl, R 4 -substituted or unsubstituted benzofuranyl, R 4 -substituted or unsubstituted furanyl, R 4 -substituted or unsubstituted pyrrolyl-2,5-dione, or R 4 -substituted or unsubstituted 2,3-dihydro-1H-indenyl;
L 1 is independently a bond or unsubstituted (C 1 -C 5 ) alkylene;
L 2 is an unsubstituted (C 1 -C 5 ) alkylene;
R 1 and R 2 are independently hydrogen, or substituted or unsubstituted (C 1 -C 5 ) alkyl;
R 3 is independently hydrogen, —OR 10 , substituted or unsubstituted (C 1 -C 5 ) alkyl, or substituted or unsubstituted 2 to 5 membered heteroalkyl;
R 4 is independently hydrogen, halogen, —CHX 2 , —CH 2 X, —OCX 3 , —OCHX 2 , oxo, substituted or unsubstituted (C 1 -C 5 ) alkyl; or substituted or unsubstituted 2 to 5 membered heteroalkyl;
R 5 is hydrogen, —CF 3 , —CN, —COOH, —CONH 2 , —CHF 2 , —CHF, substituted or unsubstituted (C 1 -C 5 ) alkyl, or substituted or unsubstituted 2 to 5 membered heteroalkyl;
R 6 is hydrogen, —CF 3 , —CN, —COOH, —CONH 2 , —CHF 2 , —CHF, substituted or unsubstituted (C 1 -C 5 ) alkyl, or substituted or unsubstituted 2 to 5 membered heteroalkyl;
R 10 and R 14 are independently hydrogen;
X is —Cl, —Br, —I, or —F.

5. A method of modulating the activity of an opioid receptor protein, said method comprising contacting said opioid receptor protein with a compound having the formula:

wherein:
W is O or S;
Ring A is independently an R 3 -substituted or unsubstituted phenyl or R 3 -substituted or unsubstituted pyridinyl;
Ring B is independently an R 4 -substituted or unsubstituted thienyl, R 4 -substituted or unsubstituted phenyl, R 4 -substituted or unsubstituted benzothienyl, R 4 -substituted or unsubstituted naphthyl, R 4 -substituted or unsubstituted benzofuranyl, R 4 -substituted or unsubstituted furanyl, R 4 -substituted or unsubstituted pyrrolyl-2,5-dione, or R 4 -substituted or unsubstituted 2,3-dihydro-1H-indenyl;
L 1 is independently a bond or unsubstituted (C 1 -C 5 ) alkylene;
L 2 is an unsubstituted (C 1 -C 5 ) alkylene;
R 1 and R 2 are independently hydrogen or substituted or unsubstituted (C 1 -C 5 ) alkyl;
R 3 is independently hydrogen, —OR 10 , substituted or unsubstituted (C 1 -C 5 ) alkyl, or substituted or unsubstituted 2 to 5 membered heteroalkyl;
R 4 is independently hydrogen, halogen, —CX 3 , —OR 14 , —CHX 2 , —CH 2 X, —OCX 3 , —OCHX 2 , oxo, substituted or unsubstituted (C 1 -C 5 ) alkyl; or substituted or unsubstituted 2 to 5 membered heteroalkyl;
R 5 is hydrogen, —CF 3 , —CN, —COOH, —CONH 2 , —CHF 2 , —CH 2 F, substituted or unsubstituted (C 1 -C 5 ) alkyl, or substituted or unsubstituted 2 to 5 membered heteroalkyl;
R 6 is hydrogen, —CF 3 , —CN, —COOH, —CONH 2 , —CHF 2 , —CHF, substituted or unsubstituted (C 1 -C 5 ) alkyl, or substituted or unsubstituted 2 to 5 membered heteroalkyl;
R 10 and R 14 are independently hydrogen;
X is —Cl, —Br, —I, or —F.

Assignees

• Univ California
• Univ Friedrich Alexander Er
• Univ Leland Stanford Junior
• Univ North Carolina Chapel Hill

Inventors

• Shoichet Brian K
• Lin Henry
• Gmeiner Peter
• Manglik Aashish
• Kobilka Brian
• Roth Bryan L
• Dengler Daniela Gisela

Classifications

• C07C275/26

  having nitrogen atoms of urea groups bound to carbon atoms of rings other than six-membered aromatic rings · CPC title

• C07C2602/08

  the other ring being five-membered, e.g. indane · CPC title

• C07D249/04

  1,2,3-Triazoles; Hydrogenated 1,2,3-triazoles · CPC title

• C07D471/04

  Ortho-condensed systems · CPC title

• A61P25/36

  Opioid-abuse · CPC title