Analgesic compounds

Patent metadata

Field	Value
Publication number	US-11242327-B2
Application number	US-201816613397-A
Country	US
Kind code	B2
Filing date	May 11, 2018
Priority date	May 15, 2017
Publication date	Feb 8, 2022
Grant date	Feb 8, 2022

Abstract

Disclosed herein are compounds of Formulae (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ik), (Im), (In), (Io), (Ip), (Iq), (Ir), (Is) and (It), methods of synthesizing compounds of Formulae (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ik), (Im), (In), (Io), (Ip), (Iq), (Ir), (Is) and (It), and methods of using compounds of Formulae (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ik), (Im), (In), (Io), (Ip), (Iq), (Ir), (Is) and (It) as an analgesic.

First claim

What is claimed is:

1. A compound selected from:

wherein:
each X 11 , each X 12 , each X 13 , and each X 14 are independently hydrogen, deuterium, an unsubstituted C 1-4 alkyl, fluoro or chloro, provided that at least two of X 11 is fluoro or chloro, provided that at least two of X 12 is fluoro or chloro, provided that at least two of X 13 is fluoro or chloro, provided that at least two of X 14 is fluoro or chloro;
each X 9 , is independently deuterium, fluoro or chloro;
R 5F , R 5H , R 5J , R 5K and R 5L are independently hydrogen, deuterium or an unsubstituted C 1-4 alkyl;
R 5C is selected from the group consisting of hydrogen, deuterium, an unsubstituted C 1-4 alkyl and C(═O)R 12 ;
R 4a and R 4b are independently hydrogen, deuterium, an unsubstituted C 1-4 alkyl, a hydroxy substituted C 1-4 alkyl or —C(X 16 ) 3 , provided that at least one of R 4a and R 4b is —C(X 16 ) 3 ;
R 12 is selected from the group consisting of hydrogen, deuterium, an unsubstituted C 1-30 alkyl and an unsubstituted C 2-30 alkenyl;
each X 16 is independently hydrogen, deuterium, an unsubstituted C 1-4 alkyl, fluoro or chloro, provided that at least two of X 16 is fluoro or chloro;
Z 1 , Z 2 and Z 3 are independently nitrogen, oxygen or sulfur;
each X E , each X L , each X N , ech X P , each X Q , each X R are independently deuterium, chloro or fluoro; and
p5, p11, p13, p14, p15 and p16 are independently 0, 1, 2, 3, 4, 5 or 6;
or a pharmaceutically acceptable salt thereof.

2. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, of Formula (Ie).

3. The compound of claim 2 , or a pharmaceutically acceptable salt thereof, wherein R 4a is —C(X 16 ) 3 ; and R 4b is hydrogen.

4. The compound of claim 2 , or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of

or a pharmaceutically acceptable salt of any of the foregoing.

5. The compound of claim 2 , or a pharmaceutically acceptable salt thereof, wherein R 5C is C(═O)R 12 .

6. A method for reducing or at least partially preventing pain or fever comprising administering an effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt thereof, to a subject in need thereof.

7. A method for reducing or at least partially preventing pain or fever comprising contacting a cell in the central and/or peripheral nervous system of a subject with an effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt thereof, to a subject in need thereof.

8. The method of claim 6 , further comprising providing at least one of an opioid analgesic and a non-steroidal anti-inflammatory drug (NSAID).

9. The method of claim 8 , wherein the opioid analgesic is selected from the group consisting of morphine, codeine, hydrocodone, oxycodone, fentanyl, pethidine, methadone, pentazocine, sufentanil, levorphanol, dihydrocodeine, nalbuphine, butorphanol, tramadol, meptazinol, buprenorphine, dipipanone, alfentanil, remifentanil, oxymorphone, tapentadol, propoxyphene and hydromorphone; and wherein the NSAID is selected from the group consisting of celecoxib, ketorolac, ketoprofen, indomethacin, sulindac, etodolac, mefenamic acid, meclofenamic acid, meclofenamate sodium, flufenamic acid, tolmetin, diclofenac, diclofenac sodium, ibuprofen, naproxen, naproxen sodium, fenoprofen, flurbiprofen, oxaprozin, piroxicam, meloxicam, ampiroxicam, droxicam, lornoxicam, cinnoxicam, sudoxicam, and tenoxicam.

10. The method of claim 6 , wherein the pain is selected from the group consisting of acute pain, post-operative pain, chronic pain, nociceptive pain, osteoarthritis, rheumatoid arthritis, neuropathic pain, migraine, visceral pain, mixed pain, lower back pain, cancer pain and fibromyalgia pain.

11. The compound of claim 2 , wherein Z 1 is sulfur.

12. The compound of claim 11 , wherein p5 is 0.

13. The compound of claim 11 , wherein R 5C is hydrogen.

14. The compound of claim 2 , or a pharmaceutically acceptable salt thereof, wherein R 4a is —C(X 16 ) 3 ; and R 4b is an unsubstituted C 1-4 alkyl.

15. The compound of claim 3 , wherein each X 16 is fluoro.

16. The compound of claim 14 , wherein each X 16 is fluoro.

17. The compound of claim 4 , or a pharmaceutically acceptable salt thereof, wherein the compound is

or a pharmaceutically acceptable salt thereof.

18. The compound of claim 4 , or a pharmaceutically acceptable salt thereof, wherein the compound is

or a pharmaceutically acceptable salt thereof.

19. The compound of claim 4 , or a pharmaceutically acceptable salt thereof, wherein the compound is

or a pharmaceutically acceptable salt thereof.

20. The compound of claim 4 , or a pharmaceutically acceptable salt thereof, wherein the compound is

or a pharmaceutically acceptable salt thereof.

21. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of

or a pharmaceutically acceptable salt of any of the foregoing.

22. The compound of claim 5 , wherein R 12 is an unsubstituted C 14-22 alkenyl.

23. The compound of claim 22 , wherein R 12 is selected from the group consisting of —(CH 2 ) 7 CH=CHCH 2 CH=CH( 2 ) 4 CH 3 , —(CH 2 ) 7 , CH=CH(CH 2 ) 7 ,CH 3 , —(CH 2 ) 7 CH=CHCH 2 CH=CH(CH 2 ) 4 CH 3 , —(CH 2 ) 7 CH=CH(CH 2 ) 7 CH 3 , —(CH 2 ) 7 CH=CHCH 2 CH=CHCH 2 CH=CHCH 2 CH 3 , —(CH 2 ) 9 CH=CH(CH 2 ) 5 CH 3 , —(CH 2 ) 3 CH=CHCH 2 CH=CHCH 2 CH=CHCH 2 CH=CH(CH 2 ) 4 CH 3 , —(CH 2 ) 11 CH=CH(CH 2 ) 7 CH 3 , —(CH 2 ) 3 CH=CHCH 2 CH=CHCH 2 CH=CHCH 2 CH=CHCH 2 CH=CHCH 2 CH 3 and —(CH 2 ) 2 CH=CHCH 2 CH=CHCH 2 CH=CHCH 2 CH=CHCH 2 CH=CHCH 2 CH=CHCH 2 CH 3 .

Assignees

• Recurium Ip Holdings Llc

Inventors

• Hopkins Chad Daniel
• Pinchman Joseph Robert
• Bunker Kevin Duane
• Slee Deborah Helen
• Boren Brant Clayton
• Kahraman Mehmet

Classifications

• C07C237/04

  the carbon skeleton being acyclic and saturated · CPC title

• C07D277/64

  with only hydrocarbon or substituted hydrocarbon radicals attached in position 2 · CPC title

• C07D239/26

  with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms · CPC title

• C07D277/28 Primary

  Radicals substituted by nitrogen atoms · CPC title

• A61K31/4184

  condensed with carbocyclic rings, e.g. benzimidazoles · CPC title