Substituted phenol compounds useful for anesthesia and sedation

Details Substituted phenol compounds useful for anesthesia and sedation Substituted phenol compounds useful for anesthesia and sedation

2002-09-26

2004-11-09

Killos, Paul J. (Department: 1625)

Organic compounds -- part of the class 532-570 series

Organic compounds

Carboxylic acid esters

C560S067000, C558S257000, C562S888000, C514S532000

Reexamination Certificate

active

06815555

ABSTRACT:

FIELD OF THE INVENTION
This invention is directed to substituted phenol compounds; pharmaceutical compositions containing substituted phenol compounds; and methods of using such compounds and compositions to induce or maintain general anesthesia or sedation in a mammal. This invention is also directed to processes and intermediates useful for preparing substituted phenol compounds.
BACKGROUND OF THE INVENTION
Propofol (i.e., 2,6-diisopropylphenol) is an injectable anesthetic used to induce and maintain general anesthesia and sedation. Because of its beneficial properties and ease of administration, propofol is widely-used for both human and veterinary applications.
One drawback of propofol is that it is retained in the body and metabolized relatively slowly. Therefore, patient recovery can be unpredictable and is often dependent on the total amount of propofol administered.
Accordingly, a need exists for novel anesthetic agents. In particular, a need exists for novel anesthetic agents having a predictable duration of action.
SUMMARY OF THE INVENTION
The present invention provides substituted phenol compounds and pharmaceutical compositions containing substituted phenol compounds, which compounds and compositions are useful for inducing and maintaining general anesthesia or sedation in a mammal. The substituted phenol compounds of this invention contain a reactive functional group which allows the compounds to be converted (i.e., hydrolyzed or metabolized) in vivo into an inactive derivative. Thus, the substituted phenol compounds of this invention have a predictable duration of action when administered to a patient.
Accordingly, in one of its composition aspects, this invention provides a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound selected from the group consisting of:
wherein
R
1
and R
2
are each independently (C
1
-C
8
)alkyl, (C
3
-C
8
)cycloalkyl, or (C
3
-C
8
)cycloalkyl(C
1
-C
8
)alkyl;
L is selected from the group consisting of covalent bond and a hydrocarbylene group containing from 1 to about 12 carbon atoms and optionally containing from 1 to about 5 heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur; and
R
3
is selected from the group consisting of —C(═O)OR
a
, —C(═O)SR
a
, —P(═O)(OR
a
)
2
, —C(═O)OCH
2
C(═O)N(R
a
)
2
, and —C(═O)OC(═O)R
a
wherein each R
a
is independently selected from a hydrocarbyl group containing from 1 to about 20 carbon atoms and optionally containing from 1 to about 5 heteroatoms selected from the group consisting of halo, nitrogen, oxygen and sulfur;
or a pharmaceutically acceptable salt thereof.
In another of its composition aspects, this invention provides a compound of formula (V):
wherein L is a covalent bond, methylene, or ethylene; and R
3
is as defined herein;
provided when L is a covalent bond, R
3
is not —C(═O)OR
a
wherein R
a
is methyl, ethyl, 1,2-dibromoethyl, but-2-enyl, hexadecyl, stearyl, or benzyl; and
provided when L is ethylene, R
3
is not —C(═O)OR
a
wherein R
a
is methyl or stearyl;
or a pharmaceutically acceptable salt thereof.
In yet another of its composition aspects, this invention provides a compound of formula (X):
wherein
R
4
is (C
1
-C
5
)alkyl, (C
2
-C
5
)alkenyl, or (C
2
-C
5
)alkynyl;
R
5
is (C
1
-C
6
)alkyl, (C
3
-C
8
)cycloalkyl, or (C
3
-C
8
) cycloalkyl(C
1
-C
6
)alkyl; and
R
6
is methyl;
or R
5
and R
6
together with the carbon atom to which they are attached form a (C
3-8
)cycloalkyl; and
R
a
is (C
1
-C
8
)alkyl, (C
2
-C
8
)alkenyl, (C
2
-C
8
) alkynyl, or (C
3
-C
8
)cycloalkyl.
The substituted phenol compounds and pharmaceutical compositions of this invention are useful for inducing or maintaining anesthesia or sedation in a mammal, such as a human or domesticated mammal.
Accordingly, in one of its method aspects, this invention is directed to a method for inducing or maintaining anesthesia or sedation in a mammal, comprising administering to a mammal an anesthesia or sedation-producing amount of a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound selected from formulae (I) or (II), or a pharmaceutically acceptable salt thereof.
The invention also provides substituted phenol compounds for use in medical therapy (e.g. for inducing or maintaining anesthesia or sedation). Additionally, this invention provides substituted phenol compounds for use in the manufacture of a medicament useful for inducing or maintaining anesthesia or sedation in a mammal (e.g. a human).
The invention also provides processes and intermediates disclosed herein that are useful for preparing substituted phenol compounds, or that are useful for preparing compositions comprising substituted phenol compounds.


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