Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
1999-08-19
2002-07-02
Jarvis, William R. A. (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S398000, C514S634000
Reexamination Certificate
active
06413962
ABSTRACT:
This invention relates to a group of receptor active compounds, primarily adrenergically active, and more particularly to compounds that contain a guanidino group or an amidino group.
It has previously been recognized that a variety of guanidine derivatives have alpha-adrenergic receptor activity in vivo. A variety of guanidine derivatives have also been used clinically as anti-hypertensive agents, including clonidine, guanabenz, guanacline, guanadrel, guanazodine, guanethidine, guanfacine and guanochlor, guanoxabenz and guanoxan.
There has recently been interest in the treatment of severe spinal trauma. The treatment has resulted in reduction of the ensuing spasticity in human, and in many spinal cord injured mammals. It has also resulted in partial or complete recovery of sensory-motor control below the trauma level. Publications by the present inventor and by others, confirming by independent tests the inventor's results with the use of clonidine, a known alpha
2
-adrenoceptor agonist, include, for example: “Functional Restoration of the Traumatically Injured Spinal Cord in Cats by Clonidine”, Naftchi, N. E., SCIENCE 217, pages 1042-1044 (1982); THE PHYSIOLOGIST, Volume 27, page 220, August, 1984, “Histochemical Correlates Of Behavioral Effect of Alpha-2 Adrenergic Agonist in Spinal Rats”, N. E. Naftchi, et al, and a more complete text provided in a paper given at the American Congress For Rehabilitation Medicine, 61st Annual Session, Oct. 23, 1984, “Newer Research in Spinal Cord Injury, Mechanism and Prevention of Acute Spinal Cord Injury” “Treatment of Mammalian Spinal Cord Injury With Antioxidants”, by N. Eric Naftchi, INT. J. DEVL. NEUROSCIENCE, vol. 9, No. 2, pp 113-126 (1991).
Clonidine and guanabenz, both alpha
2
-adrenergic receptor agonists used in the earlier work, had limited usefulness because long-term treatment with these two agents resulted in the sedation, sleepiness and desensitization of the subjects. In addition to these side effects, these agents also cause hypotension and syncopy, which tend to reduce mobility and thus delay rehabilitation and recovery of the spinal cord injured subjects. Further other side effects include constipation and rectal impaction which in tetraplegic subjects and paraplegic subjects with lesions above thoracic sixth vertebrae can paradoxically result in severe hypertension, a syndrome known as autonomic hyperreflexia.
This application further relates to new anesthetic and hypothermic agents, and more particularly to the use as general anesthetic and/or hypothermic agents, in mammals, of a previously known pharmacologic compound, guanabenz and certain of its related compounds (“guanidino compounds”). When both properties, anesthesia and hypothermia are found in the same compound, its administration results in pseudo-hibernation, that results in a relatively bloodless operating field, which can be beneficial when undergoing major surgery. These guanidino compounds also have other valuable pharmocologic properties.
Guanabenz has long been used in clinical pharmacology, generally by oral administration, as an antihypertensive agent. It is known to be a stimulant, or agonist, of central alpha
2
-adrenergic receptors, resulting in a decrease of sympathetic outflow from the brain at the bulbar level to the peripheral circulatory system.
Among the known “adverse effects” of guanabenz as an antihypertensive agent are sedation, anxiety, ataxia, depression, and sleep disturbances. Although most prior clinical use of guanabenz has involved oral administration, earlier parenteral testing in dogs had produced natriuresis, thus contraindicating long-term administration by this route for hypertension treatment.
Accidental oral overdosages of guanabenz, have not been reported to result in anesthesia; the incidents were recorded as hypotension, somnolence, lethargy, irritability, myosis and bradycardia in young children.
In U.S. Pat. No. 4,060,640, Kodama et al., described guanabenz, and its related compounds, as being central nervous system depressants that reduced hyperexcitability and induced sedation, thus overcoming psychic depression.
This alpha-adrenoceptor agonist has been shown to have a restorative effect on the central nervous system, especially in the treatment of motor and sensory functional losses due to the traumatic injury to the spinal cord (see U.S. Pat. No. 4,742,054).
GENERAL DESCRIPTION OF THE INVENTION
I. Sensory-Motor Function Restoration
It is an object of the present invention to provide novel compounds which have the capability of restoring to a mammal maximal sensory-motor function following damage to the central nervous system caused by trauma or disease. It is a further object of the present invention to provide novel compounds having such capability but without undesirable side effects which would interfere with the treatment of any mammal having suffered traumatic central nervous system injury.
A further objective of the invention, the novel compounds are efficacious anti-spastic, or spasmolytic, agents that control spasticity caused as a result of neurological damage. These drugs would also produce little or no sedation or somnolence and would not drastically lower blood pressure.
II. Anesthesia and Hypothermia
Guanidino compounds, among the alpha-adrenergic receptor agonists, are capable of inducing profound anaesthesia and/or hypothermia in mammals, when administered in a sufficient unit dosage, i.e., at least about 3 mg/kg in rats and 0.05 mg/kg in primates. In order to expedite and render more efficient the onset of anesthesia, guanabenz is preferably administered intraperitoneally (I.P.), or intravenously (I.V.), in the usual liquid vehicles, e.g., preferably a 5% aqueous dextrose solution. The guanidino compound can be provided in any of the usual pharmaceutical forms, e.g., as a physiologically acceptable salt, such as guanabenz acetate, guanabenz HCl, guanabenz maleate, or guanabenz sodium succinate, dissolved in, e.g. a 5% aqueous dextrose solution. As guanabenz and others of these guanidino compounds are capable of passing through the blood-brain barrier, unlike many non-volatile anesthetics, they need not be administered intrathecally.
The term “guanidino compounds” for both groups of activities includes any compound which has adrenergic receptor activity and which is sufficiently lipophilic to pass the blood-brain barrier in the central nervous system; and which include the moiety:
in which “n” can be an integer from 1 to 3. The above moiety can be a branched acyclic group as shown above, or the atoms “c”, N
a
, “N
b
”, or “N
c
” can be part of a cyclic group, for example, an imidazolino, a benzimidazolino, a melamine (or triazine) group, an amino-1,3-diazacyclopentene-(2), aminocaffeine, an amino-1,3-diazacyclohexene-(2), or 3,5-Diamino-1,2,4-triazole.
This guanidino moiety can be part of a xanthine group, such as in 8-aminocaffeine, or a separate group linked with a xanthine group, such as by reacting a guanidino compound with theophylline-7-acetic acid, which product possesses alpha and beta adrenergic activity. When the moiety is combined with, i.e., 5-OH-tryptamine-3,4-dihydroxyacetaldhyde, gamma-aminobutyric acid, or choline, the resulting compound, in addition to alpha adrenoceptor activity, possesses serotonergic, dopaminergic, GABA-ergic, or cholinergic activities, respectively.
In the guanidino group of Formula I, above one of N
a
, N
b
or N
c
can be replaced with a sulfur or oxygen atom, i.e., —S—, or —O—, and also obtain the desired agonist activity. When one of N
a
, N
b
or N
c
is replaced by a carbon atom (—C—), the resulting compound containing the group has an alpha-adrenergic antagonist activity, e.g., will reverse hypothermia or anesthesia induced by guanabenz, such as exemplified by compounds Nos. 96-101, 162, 163, 192, in Table I, below. These adrenergic antagonist compounds are also neuroprotective and, similar to guanidino compounds, possess glutamate (NMDA) receptor antagonistic activities.
DETAILED DESCRIPTION OF THE INVENTION
In accordance with the first aspect of t
Jarvis William R. A.
Magidoff Barry G.
LandOfFree
Guanidino compounds effective as anesthetics does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Guanidino compounds effective as anesthetics, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Guanidino compounds effective as anesthetics will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-2844305