Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Radical -xh acid – or anhydride – acid halide or salt thereof...
Reexamination Certificate
1998-03-11
2001-10-23
Raymond, Richard L. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Radical -xh acid, or anhydride, acid halide or salt thereof...
C514S567000, C562S507000, C562S576000
Reexamination Certificate
active
06306909
ABSTRACT:
BACKGROUND OF THE INVENTION
Epilepsy is a serious neurological condition, associated with seizures, that affects hundreds of thousands of people worldwide. Clinically, a seizure results from a sudden electrical discharge from a collection of neurons in the brain. The resulting nerve cell activity is manifested by symptoms such as uncontrollable movements.
A seizure is a single discrete clinical event caused by an excessive electrical discharge from a collection of neurons through a process termed “ictogenesis.” As such. a seizure is merely the symptom of epilepsy. Epilepsy is a dynamic and often progressive process characterized by an underlying sequence of pathological transformations whereby normal brain is altered, becoming susceptible to recurrent seizures through a process termed “epileptogenesis.” While it is believed that ictogenesis and epileptogenesis have certain biochemical pathways in common, the two processes are not identical. Ictogenesis (the initiation and propagation of a seizure in time and space) is a rapid and definitive electrical/chemical event occurring over seconds or minutes. Epileptogenesis (the gradual process whereby normal brain is transformed into a state susceptible to spontaneous, episodic, time-limited, recurrent seizures, through the initiation and maturation of an “epileptogenic focus”) is a slow biochemical and/or histological process which generally occurs over months to years. Epileptogenesis is a two phase process. Phase 1 epileptogenesis is the initiation of the epileptogenic process prior to the first seizure, and is often the result of stroke, disease (e.g., meningitis), or trauma, such as an accidental blow to the head or a surgical procedure performed on the brain. Phase 2 epileptogenesis refers to the process during which brain which is already susceptible to seizures, becomes still more susceptible to seizures of increasing frequency and/or severity. While the processes involved in epileptogenesis have not been definitively identified, some researchers believe that upregulation of excitatory coupling between neurons, mediated by N-methyl-D-aspartate (NMDA) receptors, is involved. Other researchers implicate downregulation of inhibitory coupling between neurons, mediated by gamma-amino-butyric acid (GABA) receptors.
Although epileptic seizures are rarely fatal, large numbers of patients require medication to avoid the disruptive, and potential dangerous, consequences of seizures. In many cases, medication is required for extended periods of time, and in some cases, a patient must continue to take prescription drugs for life. Furthermore, drugs used for the management of epilepsy have side effects associated with prolonged usage, and the cost of the drugs can be considerable.
A variety of drugs are available for the management of epileptic seizures, including older anticonvulsant agents such as phenytoin, valproate and carbamazepine (ion channel blockers), as well as newer agents such as felbamate, gabapentin, and tiagabine. &bgr;-Alanine has been reported to have anticonvulsant activity, as well as NMDA inhibitory activity and GABAergic stimulatory activity, but has not been employed clinically. Currently available accepted drugs for epilepsy are anticonvulsant agents, where the term “anticonvulsant” is synonymous with “anti-seizure” or “anti-ictogenic”; these drugs can suppress seizures by blocking ictogenesis, but it is believed that they do not influence epilepsy because they do not block epileptogenesis. Thus, despite the numerous drugs available for the treatment of epilepsy (i.e., through suppression of the convulsions associated with epileptic seizures), there are no generally accepted drugs for the treatment of the pathological changes which characterize epileptogenesis. There is no generally accepted method of inhibiting the epileptogenic process and there are no generally accepted drugs recognized as anti-epileptogenic.
SUMMARY OF THE INVENTION
This invention relates to methods and compounds useful for the treatment and/or prevention of convulsive disorders, including epilepsy.
In one aspect, the invention provides a method for inhibiting epileptogenesis in a subject. The method includes the step of administering to a subject in need thereof an effective amount of an agent which modulates a process in a pathway associated with epileptogenesis such that epileptogenesis is inhibited in the subject. In preferred embodiments,
In another aspect, the invention provides a method for inhibiting epileptogenesis in a subject. The method includes the step of administering to a subject in need thereof an effective amount of an agent which antagonizes an NMDA receptor and augments endogenous GABA inhibition, such that epileptogenesis is inhibited in the subject. In preferred embodiments, the agent antagonizes an NMDA receptor by binding to the glycine binding site of the NMDA receptors. In preferred embodiments, the agent augments GABA inhibition by decreasing glial GABA uptake. In certain preferred embodiments, the agent comprises a pharmacophore which both antagonizes an NMDA receptor and augments endogenous GABA inhibition. The agent can be administered orally and, in certain embodiments, after the step of oral administration, the agent can be transported into the nervous system of the subject by an active transport shuttle mechanism. In preferred embodiments, the anti-epileptogenic agent is a &bgr;-amino anionic compound, in which an anionic moiety is selected from the group consisting of carboxylate, sulfate, sulfonate, sulfinate, sulfamate, tetrazolyl, phosphate, phosphonate, phosphinate, and phosphorothioate. In certain embodiments, the agent is a &bgr;-amino acid, but is preferably not &bgr;-alanine.
In another aspect, the invention provides a method for inhibiting epileptogenesis in a subject. The method includes the step of administering to a subject in need thereof an effective amount of a compound of the formula:
in which A is an anionic group at physiological pH; R
1
is alkyl, alkenyl, alkynyl, cycloalkyl, aryl, alkoxy, aryloxy, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aryloxycarbonyl, amino, hydroxy, cyano, halogen, carboxyl, alkoxycarbonyloxy, aryloxycarbonyloxy or aminocarbonyl; and R
2
and R
3
are each independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, or aryloxycarbonyl; or R
2
and R
3
, taken together with the nitrogen to which they are attached, form an unsubstituted or substituted heterocycle having from 3 to 7 atoms in the heterocyclic ring; or a pharmaceutically acceptable salt thereof; such that epileptogenesis is inhibited.
In another aspect, the invention provides a method for inhibiting epileptogenesis in a subject. The method includes the step of administering to a subject in need thereof an effective amount of a compound represented by the formula:
in which the dashed line represents an optional single/double bond; A is an anionic group at physiological pH; R
2
and R
3
are each independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, or aryloxycarbonyl; or R
2
and R
3
, taken together with the nitrogen to which they are attached, form an unsubstituted or substituted heterocycle havina from 3 to 7 atoms in the heterocyclic ring; R
4
and R
5
are each independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aryloxycarbonyl, amino, hydroxy, cyano, alkoxy, aryloxy, carboxyl, alkoxycarbonyl, aryloxycarbonyl; or R
4
and R
5
, taken together, form a substituted or unsubstituted carbocyclic or heterocyclic ring having from 5 to 15 atoms in the ring; or a pharmaceutically acceptable salt thereof; such that epileptogenesis is inhibited.
In another aspect, the invention provides a method for inhibiting a convulsive disorder in a subject. The method includes the step of administering to a subject in need thereof an effective amount of a &bgr;-amino anionic compound such that the convulsive disorder is inhibited; with the proviso that t
Carran John R.
Milne Paul H.
Tan Christopher Y. K.
Weaver Donald E.
Hanley Elizabeth A.
Lahive & Cockfield LLP
Queen's University at Kingston
Rao Deepak R.
Raymond Richard L.
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