Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1999-07-12
2001-10-09
Jarvis, William R. A. (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S012200, C514S317000, C514S331000
Reexamination Certificate
active
06300332
ABSTRACT:
This invention relates generally to methods for reducing, treating, reversing or preventing drug-mediated respiratory depression, such as may be directly or indirectly caused by use of various bioactive compositions, including anaesthetics, barbiturates, analgesics, etc. The invention further relates to diarylmethyl piperazine compounds and diarylmethyl piperidine compounds, and pharmaceutical compositions thereof, having utility in medical therapy especially for reducing respiratory depression associated with certain analgesics, such as mu opiates. This invention additionally relates to diarylmethyl piperazine compounds and diarylmethyl piperidine compounds having utility in assays for determining the respiratory reducing characteristics of other bioactive compounds, including other diarylmethyl piperazine compounds and other diarylmethyl piperidine compounds.
In the study of opioid biochemistry, a variety of endogenous opioid compounds and non-endogenous opioid compounds has been identified. In this effort, significant research has been focused on understanding the mechanism of opioid drug action, particularly as it relates to cellular and differentiated tissue opiate receptors.
Opioid drugs typically are classified by their binding selectivity in respect of the cellular and differentiated tissue receptors to which a specific drug species binds as a ligand. These receptors include mu (&mgr;), delta (&dgr;), sigma (&sgr;) and kappa (&kgr;) receptors.
The well-known narcotic opiates, such as morphine and its analogs, are selective for the opiate mu receptor. Mu receptors mediate analgesia, respiratory depression, and inhibition of gastrointestinal transit. Kappa receptors mediate analgesia and sedation. Sigyma receptors mediate various biological activities.
Diarylmethyl piperazine compounds and diarylmethyl piperidine compounds having utility, for example, as analgesics, are disclosed in International Publication WO93/15062, which is incorporated by reference herein in its entirety. The present application provides for the use of compounds of such general type to treat or prevent respiratory depression.
Campa, M. J., et al., “Characterization of &dgr; Opioid Receptors in Lung Cancer Using a Novel Nonpeptidic Ligand,” Cancer Research 56, 1965-1701, Apr. 1, 1996, describes binding of [
3
H] (+)-4-[(&agr;-R)-&agr;-((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)-N,N-diethylbenzamide with membranes prepared from various small cell lung cancer cells.
There is a continuing need in the art for methods of preventing or treating respiratory depression associated with the use of various bioactive compositions, e.g., certain analgesics, anaesthetics, and barbiturates, which effect respiratory depression, either directly or indirectly.
There is also a continuing need for improved opioid compounds, particularly compounds which can reduce respiratory depression associated with the use of certain analgesics, such as mu opiate analgesic compounds, when such improved opioid compounds are administered contemporaneously with or sequential to the administration of the respiratory depression-mediating analgesic.
It is an object of the present invention to provide a bioactive compound which when administered contemporaneously with analgesics, anesthetics, barbiturates and other drugs which cause respiratory depression, acts to markedly attcntuatc such respiratory depression side effects.
SUMMARY OF THE INVENTION
The present invention relatcs to methods of treating, reducing or preventing respiratory depression in an animal, e.g., a human or non-human mammal, comprising administering to such animal an effective amount of a composition comprising a delta receptor angonist, optionally further including a mu receptor agonist compound.
Illustrative examples of suitable delta receptor agonist compounds that may be co-administered in accordance with the invention include, but are not limited to:
(+)-4-((&agr;R)-&agr;-((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)-N,N-diethylbenzamide;
[D-Pen
2
,D-Pen
5
]-(enlkephalin);
deltorphin I;
deltorphin II;
the compounds disclosed in International Patent Application Publication WO96/36620 published Nov. 21, 1996 for “Diaryldiamine Derivatives and Their Use as Delta Opioid (ant)-agonists,” the disclosure of which is hereby incorporated herein by reference; and
the compounds disclosed in International Patent Application Publication WO97/10230 published Mar. 20, 1997 for “Diarylalkenylamine Derivatives,” the disclosure of which is hereby incorporated herein by reference.
Particularly preferred delta agonist compounds from among the foregoing illustrative compounds include
(+)-4-((&agr;R)-&agr;-((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)-N,N-diethylbenzamide, and
(±)-4-((&agr;R*)-&agr;-((2R*,5S*)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)-N,N-dimethylbenzenesulfonamide (and, independently, each of the component isomers thereof, viz., (+)-4-((&agr;R)-&agr;-((2R,5S)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)-N,N-dimethylbenzenesulfonamide, and (−)-4-((&agr;R)-&agr;-((2R,5S)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)-N,N-dimethylbenzenesulfonamide).
The composition that is co-administered with the bioactive agent mediating respiratory depression may further include a mu receptor agonist such as morphine, fentanyl, alfentanil and their analogs, or the mu receptor agonists disclosed in U.S. patent application Ser. No. 08/284,445 and U.S. patent application Ser. No. 08/285,313, the disclosures of which hereby are incorporated herein by reference, including compounds therein displaying predominantly mu receptor agonist character, as well as compounds therein disclosed displaying mixed mu/delta receptor agoonism. Examples of compounds displaying such mixed mu/delta agonist character include by way of example the following compounds:
The compounds mediating respiratory depression, as mentioned above, include various analgesics, and asthetics, and barbiturates, such as for example morphine, fentanyl, midazolam, meperidine, sufentanil and codeine.
Thus, the invention contemplates co-administration with drug agents mediating respiratory depression, of delta receptor agonist compounds, optionally with further co-administration of mu receptor agonist agents, or simply compounds displaying mixed mu receptor/delta receptor agonist character, in an amount effective to combat, e.g., significantly attentuate, and preferably substantially eliminate, the respiratory depression incident to the use of the respiratory depression-mediating agent.
The invention therefore has broad utility in surgical and clinical care applications, to combat the unwanted respiratory depression side effect incident to the use of such commonly used drugs as morphine and fentanyl.
Illustrative of a preferred class of delta agonist compounds which may be usefully employed in the broad practice of the present invention are delta agonist compounds of the formula:
wherein:
Ar is a 5- or 6-member carbocyclic or heterocyclic aromatic ring with atoms selected from the group consisting of carbon, nitrogen, oxygen and sulfur, and having on a first carbon atom thereof a substituent Y and on a second ring carbon thereof a substittient R
1
,
Y is selected from the group consisting of:
hydrogen;
halogen;
C
1
-C
6
alkyl, C
2
-C
6
alkenyl, C
2
-C
6
alkynyl;
C
1
-C
6
haloalkyl;
C
1
-C
6
alkoxy;
C
3
-C
6
cycloalkoxy;
sulfides of the fomula SR
8
where R
8
is C
1
-C
6
alkyl, C
2
-C
6
alkenyl, C
2
-C
6
alkynyl, C
3
-C
6
cycloalkyl, arylalkyl having a C
5
-C
10
aryl moiety and an C
1
-C
6
alkyl moiety, or C
5
-C
10
aryl;
sulfoxides of the formula SOR
8
where R
8
is the same as above;
sulfones of the fonula SO
2
R
8
where R
8
is the same as above;
nitrile;
C
1
-C
6
acyl;
alkoxycarbonylamino (carbamoyl) of the formula NHCO
2
R
8
where R
8
is the same as above;
carboxylic acid, or an ester, amide, or salt thereof;
aminomethyl of the formula CH
2
NR
9
R
10
where R
9
and R
10
ma
Bishop Michael J.
Chang Kwen-Jen
McNutt, Jr. Robert W.
Pettit Hugh O.
Delta Pharmaceuticals, Inc.
Hultquist Steven J.
Jarvis William R. A.
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