Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2001-07-16
2004-01-20
Spivack, Phyllis G. (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S424000
Reexamination Certificate
active
06680331
ABSTRACT:
BACKGROUND OF THE INVENTION
I. Field of the Invention
The present invention relates generally to the field of anesthesiology. More particularly, it provides for the therapeutic application of lactam and thiolactam derivatives for anesthesia and conscious sedation activity.
II. Description of Related Art
There are numerous compounds presently used to provide anesthesia. Goodman and Gilman (1996) provide an overview of the field of anesthesiology as understood by those skilled in the art. However, many of the compounds in use as general anesthetic agents or for conscious sedation have a variety of problems. Compounds which are not water soluble are difficult to administer by conventional routes. Tolerances develop for some anesthetics such as benzodiazepines and opioids. Also, these compounds tend to have substantial adverse side effects and are potentially addictive. The slow onset of anesthesia is another problem with many anesthetic agents. Preferred anesthetics would have a rapid, almost instantaneous onset with a duration that can be controlled by the dose of anesthetic provided to a patient.
Sulphobenzoic acid lactam compounds for use as sedative-tranquilizing properties and hypno-anesthetics have been reported (U.S. Pat. No. 4,399,145). However, these compounds have low water solubility and a rapid onset of anesthetic properties is not mentioned.
It would therefore be advantageous to have water soluble compounds with anesthetic properties that are safe, have a rapid onset and a dose dependent duration.
SUMMARY OF THE INVENTION
Thus, the present invention contemplates therapeutic applications using lactam and thiolactam derivatives having useful anesthetic and conscious sedation activity. The lactams and thiolactams will be provided in an amount sufficient to produce anesthesia or conscious sedation.
The present invention provides a method for inducing anesthesia or conscious sedation in a patient comprising administering to the patient a composition comprising a compound having the formula:
or pharmaceutically acceptable salts thereof wherein: n is 0 or 1; Z is an 0 or S; and R
1
, R
2
, and R
3
are independently selected from the group consisting of H, an optionally substituted alkyl or alkenyl group, and an optionally substituted phenylmethyl group, with the exceptions that: R
1
and R
2
cannot both be H; when one of R
1
or R
2
is H or a methyl group, the other of R
1
or R
2
cannot be a methyl or ethyl group; and when n=1, R
1
and R
2
cannot both be ethyl. Preferably, the compound has a water solubility of at least 0.1 g per 1.0 g of water, at least 0.5 g per 1.0 g of water or even more preferably, at least 1.0 g per 1.0 g of water. The composition may comprise additional water or buffer. The compound may be administered intravenously, orally, rectally, intramuscularly, subcutaneously, through an inhalation administration, or through any other method known in the art for delivery of anesthesia or conscious sedation therapy.
It is an aspect of the current invention that the compound is given at a dosage of 1-1000 mg/kg, 100-1000 mg/kg, or from 10-100 mg/kg. The compound may be an enantiomerically enriched mixture and preferably comprises 3,3-diethyl-2-pyrrolidinone.
An aspect of the current invention is that the onset of anesthesia is rapid, where the compound produces an onset of anesthesia in less than 5 minutes, 4 minutes, 3 minutes, 2 minutes, 1 minute, 45 seconds, 30 seconds, 20 seconds, 10 seconds, or 5 seconds after administration.
DESCRIPTION OF ILLUSTRATIVE EMBODIMENTS
I. The Present Invention
The present invention provides drugs for general anesthesia and conscious sedation. More particularly, the invention relates to 3-substituted and 3,3-disubstituted 2-pyrrolidinones (&agr;-substituted and &agr;,&agr;-disubstituted &ggr;-butyrolactams), and 3-substituted and 3,3-disubstituted 2-piperidinones (&agr;-substituted and &agr;,&agr;-disubstituted &ggr;-valerolactams) and thiolactam analogs having anesthesia and conscious sedation properties.
II. Lactams and Thiolactams
Anesthetic compounds of this invention are lactams and thiolactams which can be described by the general formula:
where n is 0 or 1; Z is an oxygen or a sulfur atom; and R
1
, R
2
and R
3
are independently selected from the group consisting of H, an optionally substituted alkyl or alkenyl group, and an optionally substituted phenylmethyl group; with the exceptions that: R
1
, R
2
cannot both be H; and when one of R
1
or R
2
is H or methyl, the other of R
1
or R
2
cannot be a methyl or ethyl group.
Anesthetic compounds of formula I of this invention include lactams (formula II) and thiolactams (formula III) where n, R
1
, R
2
, and R
3
are as defined for formula I.
where lactams of formula II are generally preferred over thiolactams of formula III.
Compounds of formula I include both five- and six-member ring compounds which are exemplified by pyrrolidinones of formula IV and piperidinones of formula V:
where R
1
, R
2
, and R
3
are as defined above for formula I.
In specific aspects, this invention includes compounds of formula I and II where one of R
1
, or R
2
, is an optionally substituted phenylmethyl group as exemplified in the lactams and thiolactams of formula VI:
where n, Z, R
1
, R
2
and R
3
are as defined above for formulae I and II and R
A
, R
B
, X
1
, X
2
, X
3
, X
4
and X
5
are hydrogens or substitutents, as defined below.
In formulas I-VI, one or more of R
1
, R
2
and R
3
can be optionally substituted alkyl, alkenyl or phenylmethyl groups. Substitutents include, among others, halogen atoms, a carbonyl, cyano, hydroxy, mercapto, amino or nitro group, alkynyl, alkoxy, thioalkoxy, alkyl amine, haloalkyl or haloalkenyl group, particularly those substituents having up to about 6 carbon atoms, and preferably those substituents having from one to about 4 carbon atoms and alkyl, alkenyl or alkynyl groups substituted with one or more carbonyl, cyano, hydroxy, mercapto, amino or nitro groups, particularly those substituents having up to about 6 carbon atoms and preferably those substitutents having from 1 to about 4 carbon atoms. Preferred substitutents are those that increase the water solubility of the compounds. Compounds of formulas I-VI that are water soluble are preferred.
Optionally substituted alkyl and alkenyl groups of R
1
, R
2
and R
3
, include those which are straight-chain, branched or contain an alicyclic group, e.g., cyclopropyl, cyclobutyl, cyclohexyl, perfluoroalicyclic groups and the like.
Optionally substituted alkyl and alkenyl groups include haloalkyl and haloalkenyl groups, particularly those having from 1 to about 4 carbon atoms. Preferred haloalkyl groups and haloalkenyl groups are fluoroalkyl and fluoroalkenyl groups, respectively.
As illustrated in formulas VI, phenylmethyl groups can be substituted at the methyl carbon or on the phenyl ring. For optionally substituted phenylmethyl groups of any of R
1
, R
2
and R
3
, substituents include halogen atoms, a carbonyl, cyano, hydroxy, mercapto, amino or nitro group, an alkyl, alkenyl, alkynyl, alkoxy, thioalkoxy, alkyl amine, haloalkyl or haloalkenyl group, particularly those groups having up to about 6 carbon atoms, preferably those groups having 1 to 4 carbon atoms and alkyl or alkenyl groups substituted with one or more carbonyl, cyano, hydroxy, mercapto, amino or nitro groups, particularly those groups having up to about 6 carbon atoms and preferably those having 1 to 4 carbon atoms. Generally preferred substituents for R
1
, R
2
and R
3
groups are atoms or chemical moieties or groups that do not interfere with anesthetic or conscious sedation activity of the compound.
More specifically with respect to phenylmethyl group substituents and particularly substituents R
A
, R
B
, X
1
, X
2
, X
3
, X
4
and X
5
, these substituents, independently of one another, can, for example, be selected from the group consisting of a hydrogen, a halogen, an alkyl, an alkenyl, an alkoxy, an alkylamino, a mercapto, a thioalkyl, a thioalkoxy, a haloalkoxy, a haloalkenyl, a hydroxy, an amino, a nitro
Covey Douglas F.
Ferrendelli James A.
Board of Regents , The University of Texas System
Fulbright & Jaworski L.L.P.
Spivack Phyllis G.
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