Opioid receptor modulators

Patent metadata

Field	Value
Publication number	US-12195478-B2
Application number	US-202318297081-A
Country	US
Kind code	B2
Filing date	Apr 7, 2023
Priority date	Nov 26, 2014
Publication date	Jan 14, 2025
Grant date	Jan 14, 2025

Abstract

The present invention provides a compound having the structure wherein A is a ring structure, with or without substitution; X1 is C or N; X2 is N, O, or S; Y1 is H, -(alkyl), -(alkenyl), -(alkynyl), -(cycloalkyl), (haloalkyl), -(alkyl)-O-(alkyl) or -(alkyl)-(cycloalkyl); Y 2 is H, -(alkyl), -(alkenyl), -(alkynyl), -(cycloalkyl), (haloalkyl), -(alkyl)-O-(alkyl) or -(alkyl)-(cycloalkyl); Y3 is H-(alkyl), -(alkenyl), -(alkynyl), -(cycloalkyl), (haloalkyl), -(alkyl)-O-(alkyl) or -(alkyl)-(cycloalkyl); Y 4 is H-(alkyl), -(alkenyl), -(alkynyl), -(cycloalkyl), (haloalkyl), -(alkyl)-O-(alkyl) or -(alkyl)-(cycloalkyl); Y5 is H, -(alkyl), -(alkenyl), -(alkynyl), -(cycloalkyl), (haloalkyl), -(alkyl)-O-(alkyl) or -(alkyl)-(cycloalkyl); a and P are each present or absent and when present each is a bond.

First claim

What is claimed is:

1. A compound having the structure:

wherein
Y 1 is H, -(alkyl), -(alkenyl), -(alkynyl), —(C 3 -C 5 cycloalkyl), -(haloalkyl), -(alkyl)-O-(alkyl) or -(alkyl)-(C 3 -C 5 cycloalkyl);
Y 2 is H, -(alkyl), -(alkenyl), -(alkynyl), —(C 3 -C 5 cycloalkyl), -(haloalkyl), -(alkyl)-O-(alkyl) or -(alkyl)-(C 3 -C 5 cycloalkyl);
Y 3 is H, -(alkyl), -(alkenyl), -(alkynyl), —(C 3 -C 5 cycloalkyl), -(haloalkyl), -(alkyl)-O-(alkyl) or -(alkyl)-(C 3 -C 5 cycloalkyl);
Y 4 is H, -(alkyl), -(alkenyl), -(alkynyl), —(C 3 -C 5 cycloalkyl), -(haloalkyl), -(alkyl)-O-(alkyl) or -(alkyl)-(C 3 -C 5 cycloalkyl);
Y 5 is H, -(alkyl), -(alkenyl), -(alkynyl), —(C 3 -C 5 cycloalkyl), -(haloalkyl), -(alkyl)-O-(alkyl) or -(alkyl)-(C 3 -C 5 cycloalkyl);

R 1 , R 2 , R 3 and R 4 are each independently-H, -(alkyl), -(alkenyl), (alkynyl), -(haloalkyl), —(C 3 -C 5 cycloalkyl), -(phenyl), -(heteroalkyl), -(hydroxyalkyl), benzyl, -(alkyl)-(C 3 -C 5 cycloalkyl), -(alkyl)-OH, -(alkyl)-O-(alkyl), —OH, —NH 2 , —OAc, —CN, OCF 3 , halogen, C(O)—NH 2 , —C(O)—NH-(alkyl), C(O)—NH-(phenyl), —O-alkyl, —O-alkenyl, —O-alkynyl, —O-phenyl, —NH-alkyl, —NH-alkenyl, —NH-alkynyl, —NH-phenyl, or —C(O)—N(alkyl) 2 ; and
R 5 , R 6 , R 7 , R 8 are each independently —H, —CN, —CF 3 , —OCF 3 , -(alkyl), -(alkenyl), -(alkynyl), -(phenyl), -(heteroalkyl), -(hydroxyalkyl), —NH 2 , —NH-(alkyl), —NH-(alkenyl), —NH-(alkynyl), —NH-(phenyl), —OH, —OAc, —CO 2 H, —CO 2 -(alkyl), —O—C(O) (alkyl), —O-(alkyl), —O-(alkenyl), —O-(alkynyl), —O-(phenyl), C(O)—NH 2 , C(O)—NH-(alkyl), or C(O)—NH-(phenyl),
or an enantiomer, racemic mixture, or a pharmaceutically acceptable salt thereof.

2. The compound of claim 1 , wherein
Y 1 is H, -(alkyl), -(alkenyl), -(alkynyl), —(C 3 -C 5 cycloalkyl) or -(alkyl)-(C 3 -C 5 cycloalkyl);
Y 2 is H, -(alkyl), -(alkenyl), -(alkynyl), —(C 3 -C 5 cycloalkyl) or -(alkyl)-(C 3 -C 5 cycloalkyl);
Y 3 is H, -(alkyl), -(alkenyl), -(alkynyl), —(C 3 -C 5 cycloalkyl) or -(alkyl)-(C 3 -C 5 cycloalkyl);
Y 4 is H, -(alkyl), -(alkenyl), -(alkynyl), —(C 3 -C 5 cycloalkyl) or -(alkyl)-(C 3 -C 5 cycloalkyl);
Y 5 is H, -(alkyl), -(alkenyl), -(alkynyl), —(C 3 -C 5 cycloalkyl) or -(alkyl)-(C 3 -C 5 cycloalkyl); and
R 1 , R 2 , R 3 and R 4 are each independently H, -(alkyl), -(alkenyl), -(alkynyl), -(phenyl), -(heteroalkyl), -(hydroxyalkyl), benzyl, -(alkyl)-OH, -(alkyl)-O-(alkyl), —OH or —NH 2 .

3. The compound of claim 1 , wherein
Y 1 , Y 2 , Y 3 , Y 4 and Y 5 are each H; and
R 1 , R 2 , R 3 and R 4 are each independently H, -(alkyl), -(alkenyl), -(alkynyl), -(phenyl), -(heteroalkyl), -(hydroxyalkyl), benzyl, -(alkyl)-OH, -(alkyl)-O-(alkyl), —OH or —NH 2 .

4. The compound of claim 2 having the structure:

5. The compound of claim 3 having the structure:

6. The compound of claim 1 ,
wherein R 1 is —H and R 2 is-(alkyl), -(alkenyl), -(alkynyl), (phenyl), -(alkyl)-OH, benzyl, -(alkyl)-O-(alkyl), —OH or —NH 2 , or
wherein R 2 is —H and R 1 is -(alkyl), -(alkenyl), -(alkynyl), -(phenyl), -(alkyl)-OH, benzyl, -(alkyl)-O-(alkyl), —OH or —NH 2 .

7. The compound of claim 1 ,
wherein R 3 is-H and R 4 is-(alkyl), -(alkenyl), -(alkynyl), -(phenyl), -(alkyl)-OH, benzyl, -(alkyl)-O-(alkyl), —OH or —NH 2 , or
wherein R 4 is-H and R 3 is-(alkyl), -(alkenyl), -(alkynyl), -(phenyl), -(alkyl)-OH, benzyl, -(alkyl)-O-(alkyl), —OH or —NH 2 .

8. The compound of claim 6 ,
wherein R 3 and R 4 are each —H.

9. The compound of claim 7 ,
wherein R 1 and R 2 are each —H.

10. The compound of claim 1 ,
wherein R 1 , R 2 , R 3 and R 4 are each —H.

11. The compound of claim 1 ,
wherein R 5 , R 6 , R 7 and R 8 are each —H.

12. The compound of claim 1 ,
wherein R 5 , R 6 and R 7 are each —H and R 8 is —CN, —CF 3 , —OCF 3 , -(alkyl), -(alkenyl), -(alkynyl), -(phenyl), —NH 2 , —NH-(alkyl), —NH-(alkenyl), —NH-(alkynyl), —NH-(phenyl), —OH, —OAc, —O—C(O) (alkyl), —O-(alkyl), —O-(alkenyl), —O-(alkynyl) or —O-(phenyl); or
wherein R 5 , R 6 and R 8 are each —H and Ry is-CN, —CF 3 , —OCF 3 , -(alkyl), -(alkenyl), -(alkynyl), -(phenyl), —NH 2 , —NH-(alkyl), —NH-(alkenyl), —NH-(alkynyl), —NH-(phenyl), —OH, —OAc, —O—C(O) (alkyl), —O-(alkyl), —O-(alkenyl), —O-(alkynyl), or —O-(phenyl); or
wherein R 5 , R 7 and R 8 are each —H and R 6 is-CN, —CF 3 , —OCF 3 , -(alkyl), -(alkenyl), -(alkynyl), -(phenyl), —NH 2 , —NH-(alkyl), —NH-(alkenyl), —NH-(alkynyl), —NH-(phenyl), —OH, —OAc, —O—C(O) (alkyl), —O-(alkyl), —O-(alkenyl), —O-(alkynyl) or —O-(phenyl); or
wherein R 6 , R 7 and R 8 are each —H and R 5 is —CN, —CF 3 , —OCF 3 , -(alkyl), -(alkenyl), -(alkynyl), -(phenyl), —NH 2 , —NH-(alkyl), —NH-(alkenyl), —NH-(alkynyl), —NH-(phenyl), —OH, —OAc, —O—C(O) (alkyl), —O-(alkyl), —O-(alkenyl), —O-(alkynyl) or —O-(phenyl); or
wherein R 5 and R 8 are each —H and Re and Ry are each independently-CN, —CF 3 , —OCF 3 , -(alkyl), -(alkenyl), -(alkynyl), -(phenyl), —NH 2 , —NH-(alkyl), —NH-(alkenyl), —NH-(alkynyl), —NH-(phenyl), —OH, —OAc, —O—C(O)(alkyl), —O-(alkyl), —O-(alkenyl), —O-(alkynyl) or —O-(phenyl).

13. The compound of claim 1 having the structure:

or a pharmaceutically acceptable salt thereof.

14. The compound of claim 1 having the structure:

or a pharmaceutically acceptable salt thereof.

15. The compound of claim 1 , wherein
Y 1 is H or -(alkyl);
Y 2 is H or -(alkyl);
Y 3 is H or -(alkyl);
Y 4 is H or -(alkyl);
Y 5 is H or -(alkyl);
R 1 , R 2 , R 3 and R 4 are each independently H, -(alkyl), -(alkenyl), (alkynyl), -(phenyl), -(heteroalkyl), (hydroxyalkyl), benzyl, -(alkyl)-OH, -(alkyl)-O-(alkyl), —OH or —NH 2 ; and
R 5 , R 6 , R 7 , R 8 are each independently-H, —CN, —CF 3 , —OCF 3 , -(alkyl), -(alkenyl), -(alkynyl), -(phenyl), -(heteroalkyl), -(hydroxyalkyl), —NH 2 , —NH-(alkyl), —NH-(alkenyl), —NH-(alkynyl), —NH-(phenyl), —OH, —OAc, —CO 2 H, —CO 2 -(alkyl), —O—C(O) (alkyl), —O-(alkyl), —O-(alkenyl), —O-(alkynyl), —O-(phenyl), C(O)—NH 2 , C(O)—NH-(alkyl), or C(O)—NH-(phenyl).

16. The compound of claim 1 , wherein
Y 1 is H;
Y 2 is-(alkyl), -(alkenyl), -(alkynyl), —(C 3 -C 5 cycloalkyl), -(haloalkyl), -(alkyl)-O-(alkyl) or -(alkyl)-(C 3 -C 5 cycloalkyl);
Y 3 is H or -(alkyl);
Y 4 is H or -(alkyl);
Y 5 is H or -(alkyl);
R 1 , R 2 , R 3 and R 4 are each independently H, -(alkyl), -(alkenyl), -(alkynyl), -(phenyl), -(heteroalkyl), -(hydroxyalkyl), benzyl, -(alkyl)-OH, -(alkyl)-O-(alkyl), —OH or —NH 2 ; and
R 5 , R 6 , R 7 , R 8 are each independently-H, —CN, —CF 3 , —OCF 3 , -(alkyl), -(alkenyl), -(alkynyl), -(phenyl), -(heteroalkyl), -(hydroxyalkyl), —NH 2 , —NH-(alkyl), —NH-(alkenyl), —NH-(alkynyl), —NH-(phenyl), —OH, —OAc, —CO 2 H, —CO 2 -(alkyl), —O—C(O) (alkyl), —O-(alkyl), —O-(alkenyl), —O-(alkynyl), —O-(phenyl), C(O)—NH 2 , C(O)—NH-(alkyl), or C(O)—NH-(phenyl).

17. A pharmaceutical composition comprising the compound of claim 1 and a pharmaceutically acceptable carrier.

18. A process for producing the compound having the structure:

Assignees

• Univ Columbia

Inventors

• Kruegel Andrew C
• Wulf Madalee G
• Javitch Jonathan A
• Sames Dalibor

Classifications

• A61K47/38

  Cellulose; Derivatives thereof · CPC title

• A61K31/485

  Morphinan derivatives, e.g. morphine, codeine · CPC title

• A61K9/7092

  Transdermal patches having multiple drug layers or reservoirs, e.g. for obtaining a specific release pattern, or for combining different drugs · CPC title

• A61K9/0073

  Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy; (nasal sprays A61K9/0043; inhalation of vapours of volatile or heated drugs, e.g. essential oils or nicotine, A61K9/007; devices A61M) · CPC title

• A61K9/0002

  Galenical forms characterised by the drug release technique; Application systems commanded by energy · CPC title