Anesthetic compounds and related methods of use

Patent metadata

Field	Value
Publication number	US-9820971-B2
Application number	US-201615348790-A
Country	US
Kind code	B2
Filing date	Nov 10, 2016
Priority date	Jan 13, 2012
Publication date	Nov 21, 2017
Grant date	Nov 21, 2017

Abstract

Provided herein are compounds according to formula (I):

Provided herein is also a pharmaceutical composition comprising a compound according to formula (I) and a pharmaceutically acceptable carrier, and a method for providing anesthesia in a subject by administering such a pharmaceutical composition.

First claim

What is claimed is:

1. A method for providing anesthesia or sedation to a subject comprising administering to the subject a therapeutically effective amount of a compound according to formula (I)

wherein
R 1 is L 1 C(O)OL 2 -[C(R 7 R 8 )] p —C(R 9 R 10 )—C(O)OT;
R 2 is R 1 , optionally substituted linear or branched C 1 -C 10 alkyl, optionally substituted linear or branched C 2 -C 10 alkenyl, or optionally substituted linear or branched C 2 -C 10 alkynyl, wherein the backbone of C 1 -C 10 alkyl, C 2 -C 10 alkenyl, or C 2 -C 10 alkynyl optionally comprises one or more heteroatoms;
each R 3 is independently halogen, CN, CF 3 , SR 2 , SOR 2 , SO 2 R 2 , OR 2 , CO 2 H, CO 2 R 2 , N(R 2 ) 2 , NHR 2 , NO 2 or R 2 ;
Z is N or CR 6 ,
R 4 , R 5 , and R 6 are independently hydrogen, halogen, CN, CF 3 , SR 2 , SOR 2 , SO 2 R 2 OR 2 , CO 2 H CO 2 R 2 , N(R 2 ) 2 , NHR 2 , NO 2 or R 2 ;
R 7 and R 8 are independently hydrogen, optionally substituted linear or branched C 1 -C 10 alkyl, optionally substituted linear or branched C 2 -C 10 alkenyl, optionally substituted linear or branched C 2 -C 10 alkynyl, or R 7 and R 8 together with the carbon they are attached to form an optionally substituted 3-8 membered cyclyl or heterocyclyl;
R 9 and R 10 are independently hydrogen, optionally substituted linear or branched C 1 -C 10 alkyl, optionally substituted linear or branched C 2 -C 10 alkenyl, optionally substituted linear or branched C 2 -C 10 alkynyl, optionally substituted C 4 -C 8 cyclyl, optionally substituted C 3 -C 8 heterocyclyl, or R 9 and R 10 together with the carbon they are attached to form an optionally substituted 3-8 membered cyclyl or heterocyclyl, or
R 7 and R 9 together with the carbons they are attached to form an optionally substituted 3-8 membered cyclyl, heterocyclyl, aryl or heteroaryl;
L 1 and L 2 are independently a bond, optionally substituted linear or branched C 1 -C 10 alkylene, optionally substituted linear or branched C 2 -C 10 alkenylene, or optionally substituted linear or branched C 2 -C 10 alkynylene, wherein the backbone of C 1 -C 10 alkylene, C 2 -C 10 alkenylene, or C 2 -C 10 alkynylene optionally comprises one or more heteroatoms;
T is H, a linear or branched, substituted or unsubstituted C 1 -C 10 alkyl, linear or branched, substituted or unsubstituted C 2 -C 10 alkenyl, linear or branched, substituted or unsubstituted C 2 -C 10 alkynyl, optionally substituted cyclyl, optionally substituted heterocylcyl, optionally substituted aryl, optionally substituted heteroaryl, or PEG, wherein the backbone of C 1 -C 10 alkyl, C 2 -C 10 alkenyl, C 2 -C 10 alkynyl optionally comprises one or more heteroatoms;
n is an integer from 0-5; and
p is 0 or 1, provided that at least one of R 7 , R 8 , R 9 and R 10 is not hydrogen,
or a salt, solvate, or ester thereof.

2. The method of claim 1 , wherein the compound is administered intravenously.

3. The method of claim 2 , wherein the compound is administered as a single intravenous bolus, as a continuous intravenous infusion, or a combination thereof.

4. The method of claim 1 , wherein the subject is human.

5. The method of claim 1 , wherein R 9 and R 10 together with the carbon they are attached to form an optionally substituted 3-8 membered cyclyl or heterocyclyl.

6. The method of claim 5 , wherein Z is N.

7. The method of claim 5 , wherein R 4 and R 5 are each hydrogen.

8. The method of claim 5 , wherein R 2 is methyl, ethyl, n-propyl, isopropyl, butyl, sec-butyl, iso-butyl, tert-butyl, pentyl, neopentyl, hexyl, 2-methylpentyl, 3-methylpentyl, 2,3-dimethylbutyl, or 2,2-dimethylbutyl.

9. The method of claim 5 , wherein T is methyl or ethyl.

10. The method of claim 1 , wherein the compound has a structure of formula (IA):

or a salt, solvate, or ester thereof.

11. The method of claim 1 , wherein the compound has a structure of formula (IB):

or a salt, solvate, or ester thereof.

12. The method of claim 11 , wherein Z is N.

13. The method of claim 11 , wherein R 9 and R 10 together with the carbon they are attached to form a 3-, 4-, 5-, or 6-membered cyclyl.

14. The method of claim 1 , wherein the compound has a structure of formula (IC):

or a salt, solvate, or ester thereof.

15. The method of claim 1 , wherein the compound of formula (I) is selected from the group consisting of

or a salt, solvate, or ester thereof.

16. The method of claim 1 , wherein the compound of formula (I) is selected from the group consisting of

or a salt, solvate, or ester thereof.

17. The method of claim 1 , wherein the compound is selected from the group consisting of

or a salt, solvate, or ester thereof.

18. The method of claim 1 , wherein the compound has a structure of

or a salt, solvate, or ester thereof.

19. The method of claim 1 , wherein the compound is administered in a pharmaceutical composition comprising one or more pharmaceutically acceptable excipients.

20. The method of claim 1 , further comprising administering an analgesic agent, a paralytic agent, or both an analgesic agent and a paralytic agent.

Assignees

• Massachusetts Gen Hospital
• Annovation Biopharma Inc

Inventors

• Raines Douglas E
• Husain Syed Shaukat
• Randle John C R

Classifications

• A61P25/20

  Hypnotics; Sedatives · CPC title

• A61K31/40

  having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil · CPC title

• A61K31/4178

  not condensed 1,3-diazoles and containing further heterocyclic rings, e.g. pilocarpine, nitrofurantoin · CPC title

• C07D401/12

  linked by a chain containing hetero atoms as chain links · CPC title

• C07D403/12

  linked by a chain containing hetero atoms as chain links · CPC title