Opioid receptor modulators

Patent metadata

Field	Value
Publication number	US-10766925-B2
Application number	US-201716090102-A
Country	US
Kind code	B2
Filing date	Apr 11, 2017
Priority date	Apr 11, 2016
Publication date	Sep 8, 2020
Grant date	Sep 8, 2020

Abstract

The present invention provides compounds that can modulate opioid receptors. Some compounds of the invention are modulators of μ- and/or δ-opioid receptors. Still other compounds of the invention are opioid receptor antagonists. Some compounds of the invention can modulate opioid receptors with a significantly less likelihood of developing addiction or abuse compared to conventional opioid ligands, such as morphine. In particular, compounds of the invention are of the formula:

wherein
Ar 1 is H, optionally substituted aryl or optionally substituted heteroaryl; R 1 is a heteroalkyl; R 2 is alkyl; R 3 is an oligopeptide or a moiety of the formula —R 4 —Y; R 4 is alkylene; Y is optionally substituted heteroaryl, optionally substituted aryl or a moiety of the formula —C(═X 2 )—X 3 —R 5 ; each of X 1 , X 2 and X 3 is independently O, NR 6 or S; and each of R 5 and R 6 is independently H or alkyl.

First claim

What is claimed is:

1. A compound of the formula:

wherein
Ar 1 is H or optionally substituted heteroaryl;
R 1 is a heteroalkyl;
R 2 is alkyl;
R 3 is an oligopeptide;
R 4 is alkylene;
each of X 1 is O, NR 6 or S; and
each of R 5 and R 6 is independently H or alkyl.

2. The compound of claim 1 , wherein Ar 1 is optionally substituted pyridyl or optionally substituted pyrazyl.

3. The compound of claim 1 , wherein R 1 is a heteroalkyl of the formula:
—C(═O)—OR 7 or —R 8 —X 4 —R 9

wherein
each of R 7 and R 9 is independently H or alkyl;
R 8 is alkylene;
X 4 is O, NR 10 or S; and
R 10 is H, alkyl or a nitrogen protecting group.

4. The compound of claim 3 , wherein R 1 is a heteroalkyl of the formula: —C(═O)—OR 7 , wherein R 7 is as defined in claim 3 .

5. The compound of claim 4 , wherein R 7 is alkyl.

6. The compound of claim 3 , wherein R 1 is a heteroalkyl of the formula: —R 8 —X 4 —R 9 , wherein R 8 , X 4 and R 9 are as defined in claim 3 .

7. The compound of claim 6 , wherein R 8 is methylene.

8. The compound of claim 6 , wherein X 4 is O.

9. The compound of claim 6 , wherein R 9 is alkyl.

10. The compound of claim 1 , wherein R 3 is an oligopeptide having 3 or 4 amino acid residues.

11. The compound of claim 10 , wherein said oligopeptide is a moiety of the formula:

wherein
each of R a1 , R a2 , R a3 and R a4 is independently amino acid side-chain; and
each of R n1 , R n2 , R n3 , R n4 and R n5 is independently H, alkyl or a nitrogen protecting group.

12. The compound of claim 10 , wherein said oligopeptide is a moiety of the formula:

wherein
X is halide; and
R a3 is alkyl.

13. The compound of claim 1 , wherein said compound is a selective μ-opioid receptor agonist, a selective δ-opioid receptor agonist, or a combination thereof.

14. The compound of claim 1 , wherein said compound is an opioid receptor antagonist.

15. A method for treating pain, an opioid dependence or a clinical condition associated with an opioid overdose, said method comprising administering to a subject in need of such a treatment a therapeutically effective amount of a compound of claim 1 .

16. The method of claim 15 , wherein said clinical condition associated with an opioid overdose comprises depression of the central nervous system, depression of respiratory system or a combination thereof.

17. A method for treating a clinical condition associated with opioid receptor activation, said method comprising administering to a subject in need of such a treatment a therapeutically effective amount of a compound of claim 1 , wherein said clinical condition associated with opioid receptor activation is selected from the group consisting of: depression of the central nervous system due to opioid overdose; opioid-overdose-induced respiratory system depression; opioid abuse, addiction or development of tolerance and dependence, or a combination thereof; alcohol or cocaine abuse or addition; nicotine addiction; gambling addiction; depression; L-dopa-induced dyskinesia of Parkinson's disease; and opioid-induced gastrointestinal functional disorder.

18. The method of claim 15 , wherein said oligopeptide is a moiety of the formula:

wherein
each of R a1 , R a2 , R a3 and R a4 is independently amino acid side-chain; and
each of R n1 , R n2 , R n3 , R n4 and R n5 is independently H, alkyl or a nitrogen protecting group.

19. A compound of the formula:

wherein
Ar 1 is optionally substituted pyridyl or optionally substituted pyrazyl;
R 1 is a heteroalkyl;
R 2 is alkyl;
R 3 is an oligopeptide or a moiety of the formula —R 4 —Y;
R 4 is alkylene;
Y is optionally substituted heteroaryl, or optionally substituted aryl;
each of X 1 is O, NR 6 or S; and
each of R 5 and R 6 is independently H or alkyl.

20. The compound of claim 19 , wherein R 1 is a heteroalkyl of the formula:
—C(═O)—OR 7 or —R 8 —X 4 —R 9

wherein
each of R 7 and R 9 is independently H or alkyl;
R 8 is alkylene;
X 4 is O, NR 10 or S; and
R 10 is H, alkyl or a nitrogen protecting group.

Assignees

• Univ Arizona

Inventors

• Vardanyan Ruben
• Hruby Victor

Classifications

• C07D211/58 Primary

  attached in position 4 · CPC title

• C07K4/00 Primary

  Peptides having up to 20 amino acids in an undefined or only partially defined sequence; Derivatives thereof · CPC title

• A61K38/00

  Medicinal preparations containing peptides (peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00) · CPC title