WO2004009559A2 - Dihydrouracil compounds as anti-ictogenic or anti-epileptogenic agents - Google Patents

Abstract

Methods and compounds useful for the inhibition of convulsive disorders, including epilepsy, are disclosed. The methods and compounds of the invention inhibit or prevent or treat ictogenesis, epileptogenesis, or epileptogenesis-associated conditions. Methods for preparing the compounds of the invention are also described. Particularly preferred compounds of the invention include Formula 1 as described herein.

Description

DIHYDROURACIL COMPOUNDS AS ANTI-ICTOGENIC OR ANTI-EPILEPTOGENIC AGENTS

Related Applications

This application claims priority to U.S. Provisional Application No. 60/397,157 filed July 18, 2002, entitled "Dihydrouracil Compounds as Anti-Ictogenic or Anti-Epileptogenic Agents," the entire content of which is hereby expressly incorporated herein by reference in its entirety.

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 a normal brain is altered, becoming susceptible to recurrent seizures through a process termed "epileptogenesis."

Even though 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 a 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 or histological process, which results in the appearance of seizures which generally occur months to years following the triggering event (e.g., brain trauma). In fact, 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 an individual already susceptible to seizures, becomes still more susceptible to seizures of increasing frequency or severity. Epileptic seizures are rarely fatal, however, large numbers of patients require medication to avoid the disruptive, and potentially dangerous, consequences of seizures. In many cases, medication is required for extended periods of time, and in some cases, a patient should 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.

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. 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 like felbamate, gabapentin, and tiagabine. β-Alanine has been reported to have anticonvulsant activity, as well as activity for inhibiting NMDA receptors and stimulating GABA receptors, but has not been employed clinically. Currently available accepted drugs for epilepsy are anticonvulsant agents, where the term "anticonvulsant" is synonymous with the terms "anti-seizure" or "anti-ictogenic;" these drugs can suppress seizures by blocking ictogenesis, but it is believed that they do not block epileptogenesis. Thus, despite the numerous drugs available for the treatment of epilepsy (t.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

The present invention relates to methods and agents useful for the treatment of epilepsy and convulsive disorders, for preventing or treating epileptogenesis, and for preventing or treating ictogenesis. The invention further pertains to pharmaceutical compositions for treatment of epileptogenesis or epileptogenic conditions.

This invention provides an anti-ictogenic or anti-epileptogenic compound of the Formula I:

Formula I, wherein each R group (i.e., Rl, R^, R3, R _? R5_; gjyj R6) _may independently be a hydrogen atom, or a substituted or unsubstituted straight or branched alkyl, substituted or unsubstituted straight or branched alkoxy, substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heterocyclic, substituted or unsubstituted carbocyclic, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted aryloxyalkyl, substituted or unsubstituted arylacetamidoyl, substituted or unsubstituted alkylaryl, substituted or unsubstituted heteroaralkyl, substituted or unsubstituted alkylcarbonyl, substituted or unsubstituted arylcarbonyl, substituted or unsubstituted heteroarylcarbonyl, or substituted or unsubstituted heteroaryl group, (CR'R")o_3NR'R" (including NH2 and dialkylamino), (CR'R")o-3CN (including CN), (CR'R")θ-3NO₂ (including NO₂), halogen, (CR'R")₀. ₃C(halogen)₃, (CR'R")₀-3CH(halogen)2, (CR'R")θ-3CH₂(halogen), (CR'R")₀-3CONR'R", (CR'R")o-3S(O)i_₂NR'R", (CR'R")₀_3CHO, (CR'R")₀.3θ(CR'R")o.3H, (CR'R")₀. ₃S(O)o-2R\ (CR'R")₀.3θ(CR'R")₀.₃H, (CR'R")₀.3COR', (CR'R")₀.3CO2R' (including CO2H), or (CR'R")o-3OR' group; wherein R' and R" are each independently hydrogen, a C1-C5 alkyl, C2-C5 alkenyl, C2-C5 alkynyl, or aryl group, or R' and R" taken together are a benzylidene group or a -(CH2)_nO(CH2)_n- (where each n is 1, 2, or 3) group.

In preferred embodiments, R¹ is H or NH2; R² or R⁵ is hydrogen, halogen (e.g., bromine or chlorine), nitro, substituted or unsubstituted phenyl, substituted or unsubstituted alkoxy (e.g., methoxy), or substituted or unsubstituted alkyl (e.g., wo-propyl, «-butyl, methyl, or arylalkyl, e.g., benzyl); R^ or R^ is hydrogen, substituted or unsubstituted aryl (e.g., o- methylphenyl, /?-methylphenyl , -bromophenyl, σ-bromophenyl, m-bromophenyl, m- nitrophenyl, o-nitrophenyl, phenyl, p-nitrophenyl, m-methylphenyl, ?-methoxyphenyl, m- methyl-/>-methoxyphenyl, m-(w,/?-dichlorophenoxy)-phenyl, w-(p-chlorophenoxy)-phenyl), substituted or unsubstituted alkoxy (e.g., methoxy), or substituted or unsubstituted alkyl (e.g., benzyl, methyl, or zsO-propyl); and R^ is hydrogen, substituted or unsubstituted alkyl (e.g., iso-propyl, .sec-butylbenzyl, 7-nitrobenzyl, >-iodobenzyl, >-aminobenzyl, or arylalkyl, e.g. , benzyl), or substituted or unsubstituted phenyl (e.g., phenyl). The invention also relates to pharmaceutically acceptable salts and esters (for example, of a hydroxyl or carboxyl group) of compounds of Formula I.

The invention also includes a pharmaceutical composition comprising any of the above compounds in combination with a pharmaceutically acceptable carrier. For example, the invention includes an anti-epileptogenic or anti-ictogenic pharmaceutical composition including an amount of one or more of the above compounds effective to inhibit a convulsive disorder or condition (e.g., epilepsy) in a subject in need thereof, and a pharmaceutically acceptable carrier.

In another aspect, this invention features a method of treating or preventing ictogenesis or epileptogenesis in a subject in need thereof including administering to the subject an amount of one or more of the above compounds to inhibit ictogenesis or epileptogenesis in the subject so that ictogenesis or epileptogenesis is treated or prevented in the subject.

This invention also relates to methods and compounds useful for the treatment of epileptogenesis-associated conditions such as, for example, epilepsy, traumatic brain injury (TBI), head trauma, neurosurgery, pain, stroke, anxiety, schizophrenia, multiple sclerosis, amyotrophic lateral sclerosis, psychoses, cerebral ischemia, Huntington's chorea, motor neuron disease, Alzheimer's disease, dementia. This invention also relates to methods and compounds useful for the treatment of epilepsy. In one embodiment, the invention pertains to a method for inhibiting epileptogenesis in a subject. The method includes administering to the subject an effective amount of an anti- epileptogenic agent, such as, for example compounds of the Formulae herein (e.g., Formula I)

The invention also pertains to methods for treating a subject suffering from an epileptogenesis-associated condition. The method includes administering to the subject an effective amount of an anti-epileptogenic agent (e.g., compounds of the Formulae herein, e.g., Formula I).

In another embodiment, the invention also includes a method for preventing or treating convulsions (e.g., seizures) in a subject. The method includes administering to a subject an effective amount of an anti-epileptogenic agent (e.g., compounds of the Formulae herein).

In one embodiment, the invention pertains to pharmaceutical compositions, which include an effective amount of an anti-epileptogenic agent and a pharmaceutical acceptable carrier. The anti-epileptogenic agent may be a compound of any Formula herein (e.g., Formula I or compounds of Table 1) and pharmaceutically acceptable salts, esters,

N-substituted analogs, and prodrugs thereof. In one embodiment, the anti-epileptogenic agent has a pharmaceutically acceptable neurotoxicity.

Other anti-epileptogenic agents which may be formulated into therapeutic compositions of the invention, include, but are not limited to, compounds of the Formulae herein and pharmaceutically acceptable salts, esters, N-substituted analogs, and prodrugs thereof.

In a further embodiment, the effective amount is effective to treat an epileptogenesis- associated state in a subject. Examples of such states, include, but are not limited to, epilepsy, traumatic brain injury (TBI), head trauma, neurosurgery, pain, stroke, anxiety, schizophrenia, multiple sclerosis, amyotrophic lateral sclerosis, psychoses, cerebral ischemia, Huntington's chorea, motor neuron disease, Alzheimer's disease, and dementia.

In addition, this invention provides a kit for treating or preventing ictogenesis or epileptogenesis in a subject including one of the compounds of the invention or a metabolite thereof, and instructions for administering a therapeutically effective amount of a compound to the subject so that ictogenesis or epileptogenesis is treated or prevented in the subject. This invention further encompasses a method of diagnosing an epileptogenic condition in a subject including administering one of the above compounds labeled with a detectable marker to the subject; and measuring increased binding of the compound or a metabolite thereof to the NMDA or GABA receptors of the neurons of the subject's brain so that an epileptogenic condition is diagnosed in the subject.

This invention further relates to a method of treating or preventing seizures in a subject suffering from head trauma including administering to the subject an amount of one of the above compounds so that seizures are treated or prevented in the subject.

DETAILED DESCRIPTION OF THE INVENTION

This invention pertains to methods and agents useful for the treatment of epilepsy, convulsive disorders, and epileptogenesis associated disorders for inhibition of epileptogenesis, and for inhibition of ictogenesis; and to methods for preparing anti- convulsive and anti-epileptogenic agents of the invention. The invention further pertains to pharmaceutical compositions for treatment of convulsive disorders, and to kits including the anti-convulsive or anti-epileptogenic compounds of the invention.

For convenience, certain terms used in the specification, examples, and appended claims are collected here.

The language "a process in a pathway associated with epileptogenesis" includes biochemical processes or events which take place during Phase 1 or Phase 2 epileptogenesis and lead to epileptogenic changes in tissue, i.e., in tissues of the central nervous system (CNS), e.g., the brain. Examples of processes in pathways associated with epileptogenesis are discussed in more detail, infra.

The language "a disorder associated with NMDA receptor antagonism," includes disorders of a subject where abnormal (e.g., excessive) activity of NMDA receptors can be treated by antagonism of an NMDA receptor. Epilepsy is a disorder associated with excessive NMDA-mediated activity. Other non-limiting examples of disorders associated with excessive NMDA-mediated activity include pain, stroke, anxiety, schizophrenia, other psychoses, cerebral ischemia, Huntington's chorea, motor neuron disease, Alzheimer's disease, AIDS dementia and other disorders (in humans or animals) where excessive activity of NMDA receptors is a cause, at least in part, of the disorder. See, e.g., Schoepp et al, Eur. J. Pharmacol. 203:137-143 (1991); Leeson et al., J. Med. Chem. 34:1143-1151 (1991); Kulagowski et al., J. Med. Chem. 57:1402-1405 (1994); Mallamo et al., J. Med. Chem. 37:4438-4448 (1994); and references cited therein. The term "convulsive disorder" includes disorders or conditions where the subject suffers from convulsions, e.g., convulsions due to epileptic seizure. Convulsive disorders include, but are not limited to, epilepsy and non-epileptic convulsions, e.g., convulsions due to administration of a convulsive agent to the subject. A "convulsive disorder" may also include epileptogenesis or ictogenesis. As used herein, the word "or" is not exclusive; that is, a compound which is "anti-ictogenic or anti-epileptogenic" may be both anti-ictogenic and anti-epileptogenic.

The term "epileptogenesis-associated disorders" includes disorders of the central and peripheral nervous system that may advantageously be treated by the compounds of the invention. In an advantageous embodiment, the nervous system disorders are disorders associated or related to the process or the results of epileptogenic transformation of the brain or other nervous tissue. Examples of epileptogenesis-associated disorders include, but are not limited to, epilepsy, traumatic brain injury (TBI), head trauma, neurosurgery, pain, stroke, anxiety, schizophrenia, multiple sclerosis, amyotrophic lateral sclerosis, psychoses, cerebral ischemia, Huntington's chorea, motor neuron disease, Alzheimer's disease, dementia and other disorders (in humans or animals) in which excessive activity of NMDA receptors is a cause, at least in part, of the disorder (see, e.g., Schoepp et al., Eur. J. Pharmacol. 203:131- 243 (1991); Leeson et al, J. Med. Chem. 34:1143-1151 (1991); Kulagowski et al, J. Med. Chem. 37:1402-1405 (1994); Mallamo et α/., J Med. Chem. 37:4438-4448 (1994); and references cited therein). It should be noted that the term "disorder" is used synonymously with the terms "state" and "condition" throughout the application.

The terms "inhibiting epileptogenesis" or "inhibition of epileptogenesis" include both partial and complete reversal of epileptogenesis. It also includes prevention of epileptogenesis or a decrease or slowing in the rate of epileptogenesis (e.g., a partial or complete stop in the rate of epileptogenic transformation of the brain or central nervous system tissue). It also includes any inhibition or slowing of the rate of the biochemical processes or events which take place during Phase 1 or Phase 2 epileptogenesis and leads to epileptogenic changes in tissue, i.e., in tissues of the central nervous system (CNS), e.g., the brain. Examples of processes in pathways associated with epileptogenesis, which may be inhibited by the compounds of the invention, are discussed in more detail, infra. It also includes the prevention, slowing, halting, or reversing the process of epileptogenesis, i.e., the changes in brain tissue which result in epileptic seizures.

The term "anti-epileptogenic agent" includes agents that are capable of, for example, inhibiting epileptogenesis, suppressing the uptake of synaptic GABA, blocking GABA transporters GAT-1, GAT-2 or GAT-3, depressing glutamatergic excitation, or interacting with an NMDA receptor (e.g., at the strychnine insensitive glycine co-agonist site). Examples of anti-epileptogenic agents include compounds of the Formulae herein, and pharmaceutically acceptable salts, esters, N-substituted analogs, and prodrugs thereof.

The language "effective amount" of an anti-epileptogenic compound is that amount necessary or sufficient to treat or prevent an epileptogenesis-associated state, e.g., to prevent the various symptoms of an epileptogenesis-associated state. The effective amount can vary depending on such factors as the size and weight of the subject, the type of illness, or the particular anti-epileptogenic agent. For example, the choice of the anti-epileptogenic agent can affect what constitutes an "effective amount." One of ordinary skill in the art would be able to study the aforementioned factors and make the determination regarding the effective amount of the anti-epileptogenic agent without undue experimentation. The term "anticonvulsant agent" includes agents capable of inhibiting (e.g., preventing, slowing, halting, or reversing) ictogenesis when the agent is administered to a subject.

The term "subject" is known in the art, and includes living organisms where an immune response can be elicited, e.g., mammals. Examples of subjects include animals such as rats, mice, cats, dogs, sheep, horses, cattle, in addition to apes, monkeys, humans, and transgenic species thereof. In a preferred embodiment, the subject is a human. In certain embodiments, the subject is suffering from epilepsy, traumatic brain injury (TBI), head trauma, neurosurgery, pain, stroke, anxiety, schizophrenia, multiple sclerosis, amyotrophic lateral sclerosis, psychoses, cerebral ischemia, Huntington's chorea, motor neuron disease, Alzheimer's disease, or dementia. In general, the term "aryl" includes groups, including 5- and 6-membered single-ring aromatic groups that may include from zero to four heteroatoms, for example, benzene, phenyl, pyrrole, furan, thiophene, thiazole, isothiaozole, imidazole, triazole, tetrazole, pyrazole, oxazole, isooxazole, pyridine, pyrazine, pyridazine, and pyrimidine, and the like. "Aryl" therefore includes both heteroaromatic and non-heteroaromatic moieties, unless otherwise indicated.

Furthermore, the term "aryl" includes multicyclic aryl groups, e.g., tricyclic, bicyclic, e.g., naphthalene, benzoxazole, benzodioxazole, benzothiazole, benzoimidazole, benzothiophene, methylenedioxyphenyl, quinoline, isoquinoline, napthridine, indole, benzo uran, purine, benzofuran, deazapurine, or indolizine. Those aryl groups having heteroatoms in the ring structure may also be referred to as "aryl heterocycles," "heterocycles," "heteroaryls," or "heteroaromatics". Aryl groups may also be fused or bridged with alicyclic or heterocyclic rings which are not aromatic so as to form a polycycle (e.g., tetralin). The aromatic ring may be substituted at one or more ring positions with such substituents as described above, as for example, halogen, hydroxyl, alkyl (e.g. tolyl), alkoxy, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, alkylaminocarbonyl, arylalkyl aminocarbonyl, alkenylaminocarbonyl, alkylcarbonyl, arylcarbonyl, arylalkylcarbonyl, alkenylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylthiocarbonyl, phosphate, phosphonato, phosphinato, cyano, amino (including alkyl amino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moiety. An aryl group may also be substituted with an X group, defined elsewhere herein.

The term "substituted" includes substituents which may be placed on the moiety and which allow the molecule to perform its intended function. Examples of substituents include straight and branched chain alkyl, alkenyl, alkynyl, aryl, (CR'R")o_3NR'R" (including NH2 and dialkylamino), (CR'R")o-3CN (including CN), (CR'R")₀-3 O2 (including NO2), halogen, (CR'R")₀.3C(halogen)₃, (CR'R")₀-3CH(halogen)₂, (CR'R")₀.3CH₂(halogen), (CR'R")₀-3CONR'R", (CR'R")o-3S(O)ι_₂NR'R", (CR'R")₀-3CHO, (CR'R")₀. ₃O(CR'R")o-₃H, (CR'R")₀.3S(O)o-2R', (CR'R")₀.₃O(CR'R")₀-3H, (CR'R")₀.₃COR', (CR'R")₀.3CO2R' (including CO₂H), or (CR'R")₀-3OR' groups; wherein R' and R" are each independently hydrogen, a Ci -C5 alkyl, C2-C5 alkenyl, C2-C5 alkynyl, or aryl group, or R' and R" taken together are a benzylidene group or a -(CH2)_nO(CH2)_n- (where each n is 1 , 2, or 3) group, etc.

The term "heterocyclic" includes heteroaryls as well as any ring formed which incorporates a heteroatom or an atom which is not carbon. The ring may be saturated or unsaturated and may contain one or more double bonds. Examples of preferred heterocyclic groups include pyridyl, furanyl, thiophenyl, morpholinyl, and indolyl groups.

The term "alkyl" includes saturated aliphatic groups, including straight-chain alkyl groups (e.g., methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, etc.), branched-chain alkyl groups (isopropyl, tert-butyl, isobutyl, etc.), cycloalkyl (alicyclic) groups (cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl), alkyl substituted cycloalkyl groups, and cycloalkyl substituted alkyl groups. In certain embodiments, a straight chain or branched chain alkyl has 6 or fewer carbon atoms in its backbone (e.g., C -Cg for straight chain, C3-C6 for branched chain), and more preferably 4 or fewer. Likewise, preferred cycloalkyls have from 3-8 carbon atoms in their ring structure, and more preferably have 5 or 6 carbons in the ring structure. The terms C1 -Cg and C\. include alkyl groups containing 1, 2, 3, 4, 5, or 6 carbon atoms.

Moreover, unless otherwise specified, the term alkyl may include both "unsubstituted alkyls" and "substituted alkyls," the latter of which refers to alkyl moieties having substituents replacing a hydrogen on one or more carbons of the hydrocarbon backbone. Such substituents may include, for example, alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxy, phosphate, phosphonato, phosphinato, cyano, amino (including alkyl amino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moiety. Cycloalkyls may also be further substituted, e.g., with the substituents described above. An "alkylaryl" or an "arylalkyl" moiety is an alkyl substituted with an aryl (e.g., phenylmethyl (i.e., benzyl)). The term "alkyl" also includes the side chains of natural and unnatural amino acids. The term "«- alkyl" means a straight chain (i.e., unbranched) unsubstituted alkyl group.

The term "alkenyl" includes unsaturated aliphatic groups analogous in length and possible substitution to the alkyls described above, but that contain at least one double bond. For example, the term "alkenyl" includes straight-chain alkenyl groups (e.g., ethylenyl, propenyl, butenyl, pentenyl, hexenyl, heptenyl, octenyl, nonenyl, decenyl, etc.), branched- chain alkenyl groups, cycloalkenyl (alicyclic) groups (cyclopropenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl), alkyl or alkenyl substituted cycloalkenyl groups, and cycloalkyl or cycloalkenyl substituted alkenyl groups. In certain embodiments, a straight chain or branched chain alkenyl group has 6 or fewer carbon atoms in its backbone (e.g., C2- Cβ for straight chain, C3-C6 for branched chain). Likewise, cycloalkenyl groups may have from 3-8 carbon atoms in their ring structure, and more preferably have 5 or 6 carbons in the ring structure. The terms C2-Cg and C2-6 include alkenyl groups containing 2, 3, 4, 5, or 6 carbon atoms.

Moreover, unless otherwise specified, the term alkenyl may include both "unsubstituted alkenyls" and "substituted alkenyls," the latter of which refers to alkenyl moieties having substituents replacing a hydrogen on one or more carbons of the hydrocarbon backbone. Such substituents may include, for example, alkyl groups, alkynyl groups, halogens, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, cyano, amino (including alkyl amino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moiety. The term "alkynyl" includes unsaturated aliphatic groups analogous in length and possible substitution to the alkyls described above, but which contain at least one triple bond. For example, the term "alkynyl" includes straight-chain alkynyl groups (e.g., ethynyl, propynyl, butynyl, pentynyl, hexynyl, heptynyl, octynyl, nonynyl, decynyl, etc.), branched- chain alkynyl groups, and cycloalkyl or cycloalkenyl substituted alkynyl groups. In certain embodiments, a straight chain or branched chain alkynyl group has 6 or fewer carbon atoms in its backbone (e.g., C2-Cg for straight chain, C3-C6 for branched chain). The terms C2-Cg and C2-6 include alkynyl groups containing 2, 3, 4, 5, or 6 carbon atoms.

Moreover, unless otherwise specified, the term alkynyl may include both "unsubstituted alkynyls" and "substituted alkynyls," the latter of which refers to alkynyl moieties having substituents replacing a hydrogen on one or more carbons of the hydrocarbon backbone. Such substituents may include, for example, alkyl groups, alkynyl groups, halogens, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, cyano, amino (including alkyl amino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moiety.

Unless the number of carbons is otherwise specified, "lower alkyl" as used herein means an alkyl group, as defined above, but having from one to five carbon atoms in its backbone structure. "Lower alkenyl" and "lower alkynyl" have chain lengths of, for example, 2-5 carbon atoms.

The term "acyl" includes compounds and moieties which contain the acyl radical (CH3CO-) or a carbonyl group. The term "substituted acyl" includes acyl groups where one or more of the hydrogen atoms are replaced by, for example, an alkyl group, alkynyl group, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, cyano, amino (including alkyl amino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moiety.

The term "acylamino" includes moieties wherein an acyl moiety is bonded to an amino group. For example, the term includes alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido groups. The term "aroyl" includes compounds and moieties with an aryl or heteroaromatic moiety bound to a carbonyl group. Examples of aroyl groups include phenylcarboxy, naphthylcarboxy, etc.

The terms "alkoxyalkyl," "alkylaminoalkyl," and "thioalkoxyalkyl" include alkyl groups, as described above, which further include oxygen, nitrogen, or sulfur atoms, respectively, replacing one or more carbons of the hydrocarbon backbone, e.g. , oxygen, nitrogen, or sulfur atoms.

The term "alkoxy" includes substituted and unsubstituted alkyl, alkenyl, and alkynyl groups covalently linked to an oxygen atom. Examples of alkoxy groups include methoxy, ethoxy, isopropyloxy, propoxy, butoxy, and pentoxy groups. Examples of substituted alkoxy groups include halogenated alkoxy groups. The alkoxy groups may be substituted with groups such as alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, cyano, amino (including alkyl amino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino

(including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moieties. Examples of halogen substituted alkoxy groups include, but are not limited to, fiuoromethoxy, difluoromethoxy, trifiuoromethoxy, chloromethoxy, dichloromethoxy, trichloromethoxy, etc. The term "amine" or "amino" includes compounds or moieties in which a nitrogen atom is covalently bonded to at least one carbon or heteroatom. The term "alkyl amino" includes groups and compounds wherein the nitrogen is bound to at least one additional alkyl group. The term "dialkyl amino" includes groups wherein the nitrogen atom is bound to at least two additional alkyl groups. The term "arylamino" and "diarylamino" include groups wherein the nitrogen is bound to at least one or two aryl groups, respectively. The term "alkylarylamino," "alkylaminoaryl," or "arylaminoalkyl" refers to an amino group which is bound to at least one alkyl group and at least one aryl group. The term "alkaminoalkyl" refers to an alkyl, alkenyl, or alkynyl group bound to a nitrogen atom which is also bound to an alkyl group.

The term "amide" or "aminocarboxy" includes compounds or moieties which contain a nitrogen atom which is bound to the carbon of a carbonyl or a thiocarbonyl group. The term includes "alkaminocarboxy" groups which include alkyl, alkenyl, or alkynyl groups bound to an amino group bound to a carboxy group. It includes arylaminocarboxy groups which include aryl or heteroaryl moieties bound to an amino group which is bound to the carbon of a carbonyl or thiocarbonyl group. The terms "alkylaminocarboxy," "alkenylaminocarboxy," "alkynylaminocarboxy," and "arylaminocarboxy" include moieties wherein alkyl, alkenyl, alkynyl and aryl moieties, respectively, are bound to a nitrogen atom which is in turn bound to the carbon of a carbonyl group. The term "carbonyl" or "carboxy" includes compounds and moieties which contain a carbon connected with a double bond to an oxygen atom. Examples of moieties which contain a carbonyl include aldehydes, ketones, carboxylic acids, amides, esters, anhydrides, etc.

The term "ether" includes compounds or moieties which contain an oxygen bonded to two different carbon atoms or heteroatoms. For example, the term includes "alkoxyalkyl" which refers to an alkyl, alkenyl, or alkynyl group covalently bonded to an oxygen atom which is covalently bonded to another alkyl group.

The term "ester" includes compounds and moieties which contain a carbon or a heteroatom bound to an oxygen atom which is bonded to the carbon of a carbonyl group. The term "ester" includes alkoxycarboxy groups such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, pentoxycarbonyl, etc. The term "hydroxy" or "hydroxyl" includes groups with an -OH or -O^".

The term "halogen" includes fluorine, bromine, chlorine, iodine, etc. The term "perhalogenated" generally refers to a moiety wherein all hydrogens are replaced by halogen atoms. The terms "polycyclyl" or "polycyclic" refer to two or more cyclic rings (e.g., cycloalkyls, cycloalkenyls, cycloalkynyls, aryls or heterocyclyls) in which two or more carbons are common to two adjoining rings, e.g., the rings are "fused rings". Rings that are joined through non-adjacent atoms are termed "bridged" rings. Each of the rings of the polycycle may be substituted with such substituents as described above, as for example, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, alkoxycarbonyl, alkylaminoacarbonyl, arylalkylaminocarbonyl, alkenylaminocarbonyl, alkylcarbonyl, arylcarbonyl, arylalkyl carbonyl, alkenylcarbonyl, aminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, cyano, amino (including alkyl amino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkyl, alkylaryl, or an aromatic or heteroaromatic moiety. The term "heteroatom" includes atoms of any element other than carbon or hydrogen.

Preferred heteroatoms are nitrogen, oxygen, sulfur, and phosphorus.

It will be noted that the structures of some of the compounds of this invention include stereogenic carbon atoms. It is understood accordingly that the isomers arising from such asymmetry (e.g., all enantiomers and diastereomers) are included within the scope of this invention, unless indicated otherwise. Such isomers may be obtained in substantially pure form by classical separation techniques and by stereochemically controlled synthesis. Furthermore, the structures and other compounds and moieties discussed in this application also include all tautomers thereof.

In another embodiment, the invention includes novel compound or pharmaceutical compositions containing compounds of the invention described herein. For example, compounds and pharmaceutical compositions containing compounds set forth herein (e.g., Table 1) are part of this invention. Furthermore, novel syntheses of the compounds of the invention described herein are also included within the scope of the present invention. However, it should be noted that the reagents used in the syntheses shown herein may be altered in any manner consistent with experimentation of the ordinarily skilled artisan such that the intended compound is produced.

The compounds of the invention also include prodrugs. Prodrugs are compounds that are converted in vivo to active forms (see, e.g., R.B. Silverman, 1992, "The Organic Chemistry of Drug Design and Drug Action", Academic Press, Chp. 8). Prodrugs may be used to alter the biodistribution (e.g. , to allow compounds which would not typically enter the reactive site of a protease) or the pharmacokinetics for a particular compound. For example, a carboxylic acid group, may be esterified, e.g., with a methyl group or an ethyl group to yield an ester. When the ester is administered to a subject, the ester is cleaved, enzymatically or non-enzymatically, reductively, oxidatively, or hydrolytically, to reveal the anionic group. In addition, an anionic group may be esterified with moieties (e.g., acyloxymethyl esters) which are cleaved to reveal an intermediate compound which subsequently decomposes to yield the active compound. The prodrug moieties may be metabolized in vivo by esterases or by other mechanisms to carboxylic acids.

Prodrugs of the invention may or may not be able to interact with a biological target prior to being metabolized in vivo. However, once metabolized in vivo or in vitro the prodrug compounds of the invention are capable of performing their intended function, e.g., modulation of epileptogenesis or ictogenesis.

In one embodiment, a prodrug compound of the invention is capable of performing the intended function after being orally administered. In order to perform the intended function after oral administration, it is believed that a compound should be absorbed by a portion of the digestive tract. In one embodiment of the invention, a prodrug compound of the invention is capable of being absorbed by the digestive tract.

Examples of prodrugs and their uses are well known in the art (see, e.g., Berge et al. (1977) "Pharmaceutical Salts", J. Pharm. Sci. 66:1-19). The prodrugs may be prepared in situ during the final isolation and purification of the compounds, or by separately reacting the purified compound in its free acid form with a suitable derivatizing agent. Carboxylic acids may be converted into esters via treatment with an alcohol in the presence of a catalyst. Examples of cleavable carboxylic acid prodrug moieties include substituted and unsubstituted, branched or unbranched lower alkyl ester moieties, (e.g., ethyl esters, propyl esters, butyl esters, pentyl esters, cyclopentyl esters, hexyl esters, cyclohexyl esters), lower alkenyl esters, dilower alkyl-amino lower-alkyl esters (e.g., dimethylaminoethyl ester), acylamino lower alkyl esters, acyloxy lower alkyl esters (e.g., pivaloyloxymethyl ester), aryl esters (phenyl ester), aryl-lower alkyl esters (e.g., benzyl ester), substituted (e.g., with methyl, halo, or methoxy substituents) aryl and aryl-lower alkyl esters, amides, lower-alkyl amides, dilower alkyl amides, and hydroxy amides. This invention provides an anti-ictogenic or anti-epileptogenic compound of the

Formula I:

Formula I, wherein each R group (i.e., R}, R R3, R4_? R5_? a^j R6) _may independently be a hydrogen atom, or a substituted or unsubstituted straight or branched alkyl, substituted or unsubstituted straight or branched alkoxy, substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heterocyclic, substituted or unsubstituted carbocyclic, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted aryloxyalkyl, substituted or unsubstituted arylacetamidoyl, substituted or unsubstituted alkylaryl, substituted or unsubstituted heteroaralkyl, substituted or unsubstituted alkylcarbonyl, substituted or unsubstituted arylcarbonyl, substituted or unsubstituted heteroarylcarbonoyl, or substituted or unsubstituted heteroaryl group, (CR'R")o-3NR'R" (including NH2 and dialkylamino), (CR'R")o-3CN (including CN), (CR'R")₀-3NO₂ (including NO₂), halogen, (CR'R")₀. ₃C(halogen)₃, (CR'R")₀-3CH(halogen)₂, (CR'R")₀.3CH₂(halogen), (CR'R")₀-3CONR'R", (CR'R")o-3S(O)i_₂NR'R", (CR'R")₀-3CHO, (CR'R")₀.3O(CR'R")₀.3H, (CR'R")₀.

₃S(O)o-2R', (CR'R")o-3θ(CR'R")₀-3H, (CR'R")o. COR', (CR'R")₀-3CO₂R' (including CO2H), or (CR'R")o-3OR' group; wherein R' and R" are each independently hydrogen, a C1-C5 alkyl, C2-C5 alkenyl, C2-C5 alkynyl, or aryl group, or R' and R" taken together are a benzylidene group or a -(CH2)_nO(CH2)n^_ (where each n is 1, 2, or 3) group.

In preferred embodiments, R is H or NH2; R² or R^ is hydrogen, halogen (e.g., bromine or chlorine), nitro, substituted or unsubstituted phenyl, substituted or unsubstituted alkoxy (e.g., methoxy), or substituted or unsubstituted alkyl (e.g., wo-propyl, n-butyl, methyl, or arylalkyl, e.g., benzyl); R^ or R" is hydrogen, substituted or unsubstituted aryl (e.g., o- methylphenyl, ?-methylphenyl , -bromophenyl, o-bromophenyl, m-bromophenyl, m- nitrophenyl, o-nitrophenyl, phenyl, p-nitrophenyl, -methylphenyl, ^-methoxyphenyl, m- methyl-p-methoxyphenyl, m-(w, >-dichlorophenoxy)-phenyl, m-(p-chlorophenoxy)-phenyl), substituted or unsubstituted alkoxy (e.g., methoxy), or substituted or unsubstituted alkyl (e.g., benzyl, methyl, or wopropyl); and R^ is hydrogen, substituted or unsubstituted alkyl (e.g., z^'so-propyl, sec-butylbenzyl, -nitrobenzyl, j9-iodobenzyl, -aminobenzyl, or arylalkyl, e.g., benzyl), or substituted or unsubstituted phenyl (e.g., phenyl).

In certain embodiments, wherein one of R or R is a a naphthyl, a diphenylmethyl, or a benzene derivative substituted with three substituents selected from hydrogen, lower alkyl, halogen, nitro, amino, carboxyl, lower alkoxycarbonyl, or trifluoromethyl; and the other is a hydrogen, lower alkyl, lower alkenyl, a cyclopentyl, or a benzene derivative substituted with three substituents selected from hydrogen, lower alkyl, halogen, or trifluoromethyl; then R², R3, R5, and R^ are not all hydrogen or lower alkyl. In one embodiment, the anti-ictogenic or anti-epileptogenic compound of the invention is not compound 5.

Exemplary compounds include those in Table 1 :

Table 1 - Exemplary Compounds of the Invention

Compound #1 Compound #3

Compound #2

Compound #6

Compound #4 Compound #5

Compound #7 Compound #8 Compound #9

Compound #11 Compound #10 Compound #12

Compound #14 Compound #15

Compound #17

Compound #16 Compound #18

Compound #19 Compound #20 Compound #21

Compound #22 Compound #23 Compound #24

Compound #25 Compound #26 Compound #27

Compound #29 Compound #30

Compound #31 Compound #32 Compound #33

The use of substituted or unsubstituted dihydrouracils, and derivatives or analogs thereof, may be especially advantageous as certain uracil compounds have been found to have activity when tested in an anti-seizure model in rats. See, e.g., Medicinal Chemistry Volume V; W. J. Close, L. Doub, M. A. Spielman; Editor W. H. Hartung; John Wiley and Sons (1961). Thus, in one embodiment, and without wishing to be bound by theory, a prodrug form of the compound (a dihydrouracil) can have anti-seizure activity, while the metabolically-produced β-amino anionic compounds may have anti-epileptogenic or anti- convulsive activity. These activities, individually and in combination, can provide effective therapy for convulsive disorders in mammals (including humans). It has been reported (see, e.g., J.P. Braakhekke et al, Journal of Neurological Science, 1987; 78; 71-77) that certain uracils are enzymatically metabolized to β-alanines via dihydrouracil and β-ureidopropionate.

In fact, several of the compounds in Table 1 exhibit a protective effect when tested in a pilocarpine assay. The pilocarpine-induced seizure model was adapted from previous work published by Turski et.al. "Seizures produced by pilocarpine in mice: A behavioral, electroencephalographic and morphological analysis". Brain. Res., 1984, 321, 237-253. These tests were performed using adult male Sprague-Dawley rats in accordance with the guidelines of the Canada Council on Animal Care and under the supervision of the Queen's University Animal Care Committee. Each test compound was administered intraperitoneally at a dose of 100 mg/kg. Seizures were induced 15 minutes later by a 350 mg/kg i.p. injection of pilocarpine hydrochloride. The rat was considered protected if it exhibited no clonic spasms over the 30-minute observation period that began after pilocarpine administration. In this regard, compounds #2, #5, #9, #10, #11, #13, #29, #31, and #32 demonstrated neuroprotective activity in this pilocarpine assay (i.e., at least half of test animals were protected).

As set out above, certain embodiments of the present compounds may contain a basic functional group, such as amino or alkylamino, and are, thus, capable of forming pharmaceutically acceptable salts with pharmaceutically acceptable acids. The term "pharmaceutically acceptable salt" in this respect, refers to the relatively non-toxic, inorganic and organic acid addition salts of compounds of the present invention. These salts may be prepared in situ during the final isolation and purification of the compounds of the invention, or by separately reacting a purified compound of the invention in its free base form with a suitable organic or inorganic acid, and isolating the salt thus formed.

Representative salts include the hydrobromide, hydrochloride, sulfate, bisulfate, phosphate, nitrate, acetate, valerate, oleate, palmitate, stearate, laurate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, napthylate, mesylate, glucoheptonate, lactobionate, and laurylsulphonate salts and the like, (see, e.g., Berge et al. (1977) "Pharmaceutical Salts", J. Pharm. Sci. 66:1-19).

In other cases, the compounds of the present invention may contain one or more acidic functional groups and, thus, are capable of forming pharmaceutically acceptable salts with pharmaceutically acceptable bases. The term "pharmaceutically acceptable salt" in these instances refers to the relatively non-toxic, inorganic and organic base addition salts of compounds of the present invention. These salts may likewise be prepared in situ during the final isolation and purification of the compounds, or by separately reacting the purified compound in its free acid form with a suitable base, such as the hydroxide, carbonate or bicarbonate of a pharmaceutically acceptable metal cation, with ammonia, or with a pharmaceutically acceptable organic primary, secondary or tertiary amine. Representative alkali or alkaline earth salts include the lithium, sodium, potassium, calcium, magnesium, and aluminum salts, and the like.

Representative organic amines useful for the formation of base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine and the like. In one aspect, the invention provides methods for treating convulsive disorders, including epilepsy with compounds according to Formula I.

The invention provides a method for inhibiting epileptogenesis in a subject. The method includes 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.

As noted above, upregulation of excitatory coupling between neurons, mediated by N- methyl-D-aspartate (NMDA) receptors, and downregulation of inhibitory coupling between neurons, mediated by gamma-amino-butyric acid (GABA) receptors, have both been implicated in epileptogenesis. Other processes in pathways associated with epileptogenesis include release of nitric oxide (NO), a neurotransmitter implicated in epileptogenesis; release of calcium (Ca ), which may mediate damage to neurons when released in excess; neurotoxicity due to excess zinc (Zn²⁺); neurotoxicity due to excess iron (Fe²⁺); and neurotoxicity due to oxidative cell damage. Accordingly, in certain embodiments, an agent to be administered to a subject to inhibit epileptogenesis preferably is capable of inhibiting one or more processes in at least one pathway associated with epileptogenesis. For example, an agent useful for inhibition of epileptogenesis can reduce the release of, or attenuate the epileptogenic effect of, NO in brain tissue; antagonize an NMDA receptor; augment endogenous GABA inhibition; reduce the release of, reduce the free concentration of (e.g., by chelation), or otherwise reduce the epileptogenic effect of cations including Ca²⁺, Zn²⁺, or Fe²⁺; inhibit oxidative cell damage; or the like. In certain embodiments, an agent to be administered to a subject to inhibit epileptogenesis is capable of inhibiting at least two processes in at least one pathway associated with epileptogenesis.

In one embodiment, the agent antagonizes an NMDA receptor and augments endogenous GABA inhibition. In certain embodiments, the agent is administered orally. Preferably, after oral administration, the agent is transported to the nervous system of the subject by an active transport shuttle mechanism. A non- limiting example of an active transport shuttle is the large neutral amino acid transporter, which is capable of transporting amino acids across the blood-brain barrier (BBB).

In certain embodiments, an active agent of the invention antagonizes NMDA receptors by binding to the glycine binding site of the NMDA receptors. In certain embodiments, the agent augments GABA inhibition by decreasing glial GABA uptake. In a particular embodiment, an anti-epileptogenic agent of the invention may antagonize NMDA receptors by interacting, e.g., binding, to the glycine binding site of the NMDA receptors. In another embodiment, the agent augments GABA inhibition by decreasing glial GABA uptake. For example, in certain embodiments the agent modulates, e.g., blocks, the GAT-1, GAT-2, or GAT-3 transporters. In certain other embodiments, the anti-epileptogenic agent modulates, e.g., inhibits, GABA transaminase. In yet another embodiment of the invention, anti- epileptogenic agent is a glutamatergic excitation modulator, e.g., inhibitor. In particular embodiments, the agent is administered orally. In yet other embodiments, the method further includes administering the agent in a pharmaceutically acceptable vehicle. In particular other embodiments, the method further includes administering the agent in a pharmaceutically acceptable vehicle, e.g., such that the anti-epileptogenic agent is suitable, e.g., for oral administration.

The term "anti-epileptogenic agent" includes agents which are capable of, for example, inhibiting epileptogenesis; suppressing, e.g., inhibiting, the uptake of synaptic

GABA; blocking GABA transporters GAT-1, GAT-2 or GAT-3; depressing, e.g., inhibiting, glutamatergic excitation; or interacting with an NMDA receptor (e.g., at the strychnine insensitive glycine co-agonist site).

The term "modulate" includes the act of upregulation (e.g., enhancement) or inhibition of a designated activity, e.g. , the action of an enzyme or biological pathway. For example, the act of modulating GABA transaminase includes the inhibition as well as the upregulation of GABA transmaminase.

The step of administering to the subject can include administering to the subject a compound that is metabolized to an anti-convulsant or anti-epileptogenic compound of the invention. For example, the methods of the invention include the use of prodrugs which are converted in vivo to the therapeutic compounds of the invention. See, e.g., Silverman, ch. 8, op cit.. Such prodrugs can be used to alter the biodistribution to allow compounds that would not typically cross the blood-brain barrier to cross the blood-brain barrier, or the pharmacokinetics of the therapeutic compound. For example, an anionic group, e.g., a carboxylate group, can be esterified with an ethyl or a fatty group to yield a carboxylic ester. When the carboxylic ester is administered to a subject, the ester can be cleaved, enzymatically or non-enzymatically, to reveal the anionic group.

In another embodiment, the invention provides a method for inhibiting both a convulsive disorder and epileptogenesis in a subject. The method includes the step of administering to a subject in need thereof an effective amount of an agent which a) blocks sodium or calcium ion channels, or opens potassium or chloride ion channels; and b) has at least one activity selected from the group consisting of NMDA receptor antagonism; augmentation of endogenous GABA inhibition; calcium binding; iron binding; zinc binding; NO synthase inhibition; and antioxidant activity; such that epileptogenesis is inhibited in the subject.

Compounds, as described herein, e.g., dihydrouracil compounds of Formula I, which find use in the therapeutic methods of the invention, can be determined through screening assays known in the art. Chronic epileptogenesis can be modeled in rats (and candidate compounds screened with) the kindling assay described by Silver et al. (Ann. Neurol. (1991) 29:356). Similarly, compounds useful as anticonvulsants can be screened in conventional animal models, such as the mouse model described in Horton, R.W. et al, Eur. J. Pharmacol. (1979) 59:75-83. Compounds or pharmacophores useful for, e.g., binding to or inhibition of receptors or enzymes can be screened according to conventional methods known to the ordinarily skilled practitioner. For example, binding to the GABA uptake transporter can be quantified by the method of Ramsey et al. as modified by Schlewer (Schlewer, J., et al, J. Med. Chem. (1991) 34:2547). Binding to the glycine site on an NMDA receptor can be quantified, e.g., according to the method described in Kemp, A., et al, Proc. Natl. Acad. Sci. USA (1988) 85:6547. Effect on the voltage-gated Na⁺ channel can be evaluated in vitro by voltage clamp assay in rat hippocampal slices.

Compounds useful in the present invention may also include carrier or targeting moieties which allow the therapeutic compound to be selectively delivered to a target organ or organs. For example, if delivery of a therapeutic compound to the brain is desired, the compound may include a moiety capable of targeting the compound to the brain, by either active or passive transport (a "targeting moiety"). For example, the carrier molecule may include a redox moiety, as described in, for example, U.S. Patent Nos. 4,540,564 and 5,389,623. These patents disclose drugs linked to dihydropyridine moieties which can enter the brain, where they are oxidized to a charged pyridinium species which is trapped in the brain. Other carrier moieties include compounds, such as amino acids or thyroxine, which can be passively or actively transported in vivo. Such a carrier moiety can be metabolically removed in vivo, or can remain intact as part of an active compound. Many targeting moieties are known, and include, for example, asialoglycoproteins (see, e.g., U.S. Patent No. 5,166,320) and other ligands which are transported into cells via receptor-mediated endocytosis.

The targeting and prodrug strategies described above can be combined to produce a compound that can be transported as a prodrug to a desired site of action and then unmasked to reveal an active compound.

The invention further provides a kit which includes a compound of the invention and instructions for administering a therapeutically effective amount of the compound to a subject in need thereof such that a convulsive disorder (e.g., epileptogenesis) is inhibited in the subject. The kits of the invention provide convenient means for administering the compounds of the invention. In a particularly preferred embodiment, the kit includes a therapeutically effective amount of the compound, more preferably in unit dosage form.

In another aspect, the present invention provides pharmaceutically acceptable compositions which comprise a therapeutically-effective amount of one or more of the compounds described above, formulated together with one or more pharmaceutically acceptable carriers (additives) or diluents. The pharmaceutical compositions of the present invention may be specially formulated for administration in solid or liquid form, including those adapted for the following: (1) oral administration, for example, drenches (aqueous or non-aqueous solutions or suspensions), tablets, boluses, powders, granules, pastes for application to the tongue; (2) parenteral administration, for example, by subcutaneous, intramuscular or intravenous injection as, for example, a sterile solution or suspension; (3) topical application, for example, as a cream, ointment, patch, or spray applied to the skin; or (4) intravaginally or intrarectally, for example, as a pessary, cream or foam. In a preferred embodiment, the therapeutic compound is administered orally. The compounds of the invention can be formulated as pharmaceutical compositions for administration to a subject, e.g., a mammal, including a human. The compounds of the invention are administered to subjects in a biologically compatible form suitable for pharmaceutical administration in vivo. By "biologically compatible form suitable for administration in vivo" is meant a compound to be administered where any toxic effects are outweighed by the therapeutic effects of the compound. Administration of a therapeutically active amount of the therapeutic compositions of the present invention is defined as an amount effective, at dosages and for periods of time necessary to achieve the desired result. For example, a therapeutically active amount of a compound of the invention may vary according to factors such as the disease state, age, sex, and weight of the individual, and the ability of compound to elicit a desired response in the individual. Dosage regimes may be adjusted to provide the optimum therapeutic response. For example, several divided doses may be administered daily or the dose may be proportionally reduced as indicated by the exigencies of the therapeutic situation.

The active compound may be administered in a convenient manner such as by injection (subcutaneous, intravenous, etc.), oral administration, inhalation, transdermal application, or rectal administration. Depending on the route of administration, the active compound may be coated in a material to protect the compound from the action of enzymes, acids and other natural conditions which may inactivate the compound.

A compound of the invention can be administered to a subject in an appropriate carrier or diluent, co-administered with enzyme inhibitors or in an appropriate carrier such as liposomes. The term "pharmaceutically acceptable carrier" as used herein includes diluents such as saline and aqueous buffer solutions. To administer a compound of the invention by other than parenteral administration, it may be necessary to coat the compound with, or co- administer the compound with a material to prevent its inactivation. Liposomes include water-in-oil-in-water emulsions as well as conventional liposomes (Strejan et al, (1984) J. Neuroimmunol 7:27). The active compound may also be administered parenterally or intraperitoneally. Dispersions can also be prepared in glycerol, liquid polyethylene glycols, and mixtures thereof and in oils. Under ordinary conditions of storage and use, these preparations may contain a preservative to prevent the growth of microorganisms.

Pharmaceutical compositions suitable for injection, include sterile aqueous solutions (where water soluble) or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersion. In all cases, the composition should be sterile and should be fluid to the extent that easy syringability exists. It should be stable under the conditions of manufacture and storage and should be preserved against the contaminating action of microorganisms such as bacteria and fungi. The pharmaceutically acceptable carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyetheylene glycol, and the like), and suitable mixtures thereof. The proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion, and by the use of surfactants. Prevention of the action of microorganisms can be achieved by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, ascorbic acid, thimerosal, and the like. In many cases, it will be preferable to include isotonic agents, for example, sugars, polyalcohols such as mannitol, sorbitol, sodium chloride in the composition. Prolonged absorption of the injectable compositions can be brought about by including in the composition an agent which delays absorption, for example, aluminum monostearate and gelatin.

Sterile injectable solutions can be prepared by incorporating active compound in the required amount in an appropriate solvent with one or a combination of ingredients enumerated above, as required, followed by filter sterilization. Generally, dispersions are prepared by incorporating the active compound into a sterile vehicle that contains a basic dispersion medium and the required other ingredients from those enumerated above. In the case of sterile powders for the preparation of sterile injectable solutions, the preferred methods of preparation are vacuum drying and freeze-drying which yields a powder of the active ingredient plus any additional desired ingredient from a previously sterile-filtered solution thereof.

When the active compound is suitably protected, as described above, the composition may be orally administered, for example, with an inert diluent or an assimilable edible carrier. As used herein "pharmaceutically acceptable carrier" includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like. The use of such media and agents for pharmaceutically active substances is well known in the art. Except insofar as any conventional media or agent is incompatible with the active compound, use thereof in the therapeutic compositions is contemplated. Supplementary active compounds can also be incorporated into the compositions.

It is especially advantageous to formulate parenteral compositions in dosage unit form for ease of administration and uniformity of dosage. Dosage unit form as used herein refers to physically discrete units suited as unitary dosages for the mammalian subjects to be treated; each unit containing a predetermined quantity of active compound calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier. The specification for the dosage unit forms of the invention are dictated by and directly dependent on (a) the unique characteristics of the active compound and the particular therapeutic effect to be achieved, and (b) the limitations inherent in the art of compounding such an active compound for the therapeutic treatment of individuals.

EXAMPLES

The following examples are presented so that the skilled artisan may better understand some aspects of the present invention, and they should not be interpreted as limiting. For example, one skilled in the art will readily recognize that similar compounds may be synthesized in analogous manner as those described herein below, and those analogous compounds are within the scope of the present invention.

Reagents and solvents were obtained from Sigma Aldrich. Solvents such as methanol, ethanol, dichloromethane, tetrahydrofuran and pyridine were dried/purified as described by Perrin, Perrin and Armarego, and references therein. Thin layer chromatography was performed using pre-coated Brinkmann silica gel 60 F_{2 4} plates with aluminium backing. TLCs were visualized using ultraviolet light, iodine vapour or ninhydrin. Proton and carbon NMR were performed on a Bruker Avance 300 (300 MHz), or Bruker Ac-200 (200 MHz) spectrometer. 1H NMR were recorded at 300 MHz unless otherwise specified. Chemical shifts are reported as δ parts per million downfield of tetramethylsilane (TMS). Infrared spectra (IR) were recorded on a Bomem MB- 120 spectrophotometer; samples were prepared as KBr disks. Melting points were determined using a Mel-Temp II capillary apparatus and are uncorrected.

General Procedure for the synthesis of N-l -substituted Dihydrouracil Analogues Addition of a substituted amine to acrylonitrile: 3-isopropylamino-propionitrile:

Isopropylamine (8.6 mL, 0.1 mol) was cooled in an ice bath to 0°C, under argon. Acrylonitrile (6.5 mL, 0.1 mol) was added to the amine via a dropping funnel and the reaction stirred at 0°C for five hours, then refluxed for two hours. The reaction mixture was then left to sit at room temperature, without stirring, overnight. The excess amine was removed under reduced pressure and the resulting oil, (6.6 g, 59% yield) was used without further purification.

3-(sec)-Butylamino-propionitrile: Prepared in quantitative yield as a colourless oil from (sec)-butylamine (13.9 mL, 0.137 mol) and acrylonitrile (6.0 mL, 0.091 mol). Addition of Cyanogen Bromide to Substituted Aminopropionitrile: Method A

2-(Cyanoethyl)methylcyanamide: Cyanogen bromide (2.5 g, 0.024 mol) was dissolved in dry THF and the solution cooled to -10°C in a CO₂/acetone bath. N-Methyl-β- alaninenitrile (2.2 mL, 0.024 mol), and triethylamine (3.3 mL, 0.024 mol) were added and the reaction stirred at -10°C for two hours. The reaction was then warmed to room temperature and left to stir overnight, under argon. The solvent was removed under reduced pressure and the residue dissolved in ether and washed with 10% aqueous citric acid and water. The organic layer was dried over sodium sulfate and the solvent removed under reduced pressure. The resulting oil (0.73 g, 28% yield) was used without further purification.

Addition of Cyanogen Bromide to Substituted Aminopropionitrile: Method B

Benzyl-(2-cyanoethyl)-cyanamide: To a solution of cyanogen bromide (3.3 g, 0.031 mol) and sodium acetate (2.5 g, 31 mmol) in 50 mL of dry ethanol was added N- benzylaminopropionitrile (3.3g, 31 mmol). The reaction was left to stir overnight at room temperature, under argon. The solvent was removed under reduced pressure and the resulting solid dissolved in ether and washed with 10% citric acid, then water. The organic layer was dried over sodium sulfate and the solvent removed under reduced pressure to yield a colourless oil (3.4 g, 59% yield), and used without further purification.

2-(Cyanoethyl)-isopropyl-cyanamide: Prepared as a colorless oil in 59% yield from of N-isopropylaminopropionitrile (3g, 0.024 mol), cyanogen bromide (2.8 g, 0.024 mol) and sodium acetate (1.97 g, 0.024 mol).

(sec)-Butyl-(2-cyanoethyl)-2-cyanamide: Prepared as a colourless oil in 84% yield from (sec)-butylaminopropionitrile (5g, 0.024 mol), cyanogen bromide (6.3 g, 0.059 mol) and sodium acetate (3.3 g, 0.04 mol). (2-Cyanoethyl)-phenyl-cyanamide: Prepared as a colourless oil in 32% yield from 3- anilinopropionitrile (5g, 0.024 mol), cyanogen bromide (5.4 g, 0.051 mol) and sodium acetate (2.8 g, 0.034 mol). Cyclization of substituted cyanamide to dihydrouracil, Method A: l- Methyl-5,6-dihydropyrimidine-2,4-dione: 2-(Cyano-ethyl)-methyl-cyanamide (726 mg, 6.7 mmol) was dissolved in 4.6M aq. HCl and refluxed for 2 hours. The reaction was gradually cooled to 0°C, and the resulting crystals collected by filtration. The product was purified by recrystallization.

Cyclization of substituted cyanamide to dihydrouracil, Method B: l- Isopropyl-5,6-dihydropyrimidine-2,4-dione: 2-(cyano-ethyl)-isopropyl-cyanamide (2.2 g, 0.016 mol), was dissolved in a 1:1 (v) solution of cone. HCl and water, then refluxed for 1 .75 hours. The solvent was removed under reduced pressure and the residue dissolved in hot THF. An insoluble salt was removed by filtration, and the filtrate evaporated to dryness under reduced pressure to yield a white solid, purified by recrystallization. l-Methyl-5,6-dihydropyrimidine-2,4-dione: Prepared as a white solid in 66% yield from (2-cyano-ethyl)-methyl-cyanamide as described in method A. m.p. = 173-175°. 1H- NMR (DMSO) δ: 2.5 (t, 2H, J= 6.9 Hz), 2.8 (s, 3H), 3.3 (t, 3H, J= 6.9), 7.3 (s, IH), 10.1 (s, IH).

1- Phenyl-5,6-dihydropyrimidine-2,4-dione: Prepared as a white solid in 80% yield as described in method A from (2-cyano-ethyl)-phenyl-cyanamide (548 mg, 3.2 mmol). m.p. = 191-192°C. 1H-NMR (DMSO) δ: 2.7 (t, 2H, J= 6.6 Hz), 3.8 (t, 2H, J- 6.6Hz), 7.2-7.4 (m, 5H), 10.4 (s, IH).

1- Benzyl-5,6-dihydropyrimidine-2,4-dione: Prepared as a white solid in 74% yield as described in method A from (2-cyano-ethyl)-benzyl-cyanamide (403 mg, 2.18 mmol). m.p. = 127-128°C. Η-NMR, 200 MHz, (DMSO) δ: 2.6 (t, 2H, J= 6.9 Hz), 3.3 (t, 2H, J= 6.9 Hz), 4.6 (s, 2H), 7.3 (m, 5H), 10.3 (s, IH). l-Isopropyl-5,6-dihydropyrimidine-2,4-dione: Prepared as a white solid in 61% yield from 2-(cyano-ethyl)-isopropyl-cyanamide (2.2, 0.016 mol) as described in method B. m.p. = 143-145°C. 1H-NMR (DMSO) δ: 1.1 (d, 6H, J= 7.2 Hz), 2.5 (t, 2H, J= 6.8 Hz), 3.2 (t, 2H, J= 6.8), 4.4 (septuplet, IH, J= 6.8 Hz), 10.0 (s, IH). l-(sec)-Butyl-5,6-dihydropyrimidine-2,4-dione: Prepared as a white solid in 48% yield as described in method B from (sec)-butyl-(2-cyanoethyl)-2-cyanamide (5.1 g, 0.037 mol). Yield = 48%. m.p. = 100-101°C. I.R. λ (cm^"1) 3625, 2563, 1551. TLC (R_f): 3:2:1 Hexanes:EtOAc:MeOH = 0.2. 1H-NMR (CDC1₃) δ: 0.9 (t, 3H, J= 7.5 Hz), 1.1 (d, 3H, J=6.6 Hz), 1.5 (quintet, 2H, J= 7.5 Hz), 2.6 (t, 2H, J= 6.6 Hz), 3.3 (m, 2H), 4.4 (m, 2H), 8.6 (s, IH); ¹³C NMR: 170.0, 152.9, 50.1, 35.4, 31.0, 26.6, 17.6, 10.9. Mass Spec. (ES⁺) = 170.2. High Res. C₈H_MN₂O₂ requires 170.105, found 170.10543.

Bromination ofl- Benzyl-5,6-dihydropyrimidine-2,4-dione: l-Benzyl-2,4-dihydro- pyrimidinedione, (lg, 5 mmol) was refluxed in ten times its weight of acetic acid, (10 mL). Bromine, (0.25 mL, 5 mmol), also in ten times its weight in acetic acid (2.5 mL), was added via a dropping funnel. The solution was left to reflux for eight hours, or until it became a pale yellow color. The acetic acid was removed under reduced pressure and the resulting yellow residue dissolved in water. It was then neutralized to pH 5 using a 10% aqueous solution of NaOH. A brown solid was collected by filtration, and recrystallized in ethanol. Yield - 28%. m.p. = 161-162°C. 1H NMR, 200MHz, (DMSO) δ: 3.5 (dd, IH, J_AX= 3.2 Hz, J_AB= 15 Hz), 4.0 (dd, IH, J_BX= 3.5 Hz, J_BA= 15 Hz), 4.6 (s, 2H), 4.8 (t, IH, J= 3.1 Hz), 7.4 (m, 5H), 10.7 (s, IH).

Procedure for the Catalytic Hydrogenation of Thymine and 6-Methyluracil: Dihydrothymine: Thymine, (300 mg, 2.4 mmol) was dissolved in distilled water and

312 mg of 5% Rh on alumina was added. The flask was flushed with H₂, and subsequently allowed to stir under a hydrogen balloon for 6 hours and monitored by TLC. The catalyst was then removed by gravity filtration and the filtrate removed under reduced pressure. The resulting white solid was recrystallized from ethanol in 56% yield. Yield = 56%. m.p. = 264- 265°C. Η NMR (D₂O) δ: 1.1 (d, 3H, J=7.2 Hz), 2.7 (m, IH), 3.1 (dd, IH, J_AB= 12.8 Hz, J_AX= 10.1 Hz), 3.4 (dd, IH, J_Bχ= 6.3 Hz, J_BA= 12.8 Hz).

6-Methyl-5,6-Dihydropyrimidine-2,4-Dione: Prepared as a white solid in 60% yield by the method described above from 6-methyluracil, (200 mg, 1.6 mmol) and 200 mg of 5% Rh on alumina catalyst, m.p. = 221-222°C. 1H NMR (D₂O) δ: 1.1 (d, 3H, J= 6.3 Hz), 2.3 (dd, IH, J_AB = 16.9 Hz, JAX = 9.4Hz), 2.6 (dd, 1 H, J_BX = 5.1 Hz, J_AB = 16.9 Hz), 3.7 (m, IH). 5-Nitro-6-Methyl-5,6-Dihydropyrimidine-2,4-Dione: 6-Methyl-pyrimidine-2,4- dione, (6. 36 g, 50 mmol) was added slowly to 30 mL of cold 98% H₂SO₄. KNO₃ (5.2 g, 51.5 mmol) was added, and the reaction left to stir at 0°C for 30 minutes. The reaction mixture was warmed to room temperature and left to stir for two hours. It was then poured over ice, and the yellow precipitate collected by filtration and recrystallized first in methanol, then ethanol. Yield = 36%. m.p. = 280-281°C (dec). 1H NMR (DMSO) δ: 2.3 (s, 3H), 11.78 (s, IH), 11.81 (s, IH).

5-Nitro-6-Methyl-5,6-Dihydropyrimidine-2,4-Dione: NaBH₄ (1.19 g, 0.03 mol) was added slowly to a solution of 6-methyl-5-nitro-lH-pyrimidine-2,4-dione, (1 g, 8 mmol) in 32 mL methanol and 88 mL of water. The reaction was left to stir for one hour at room temperature. A white precipitate was collected by filtration, then dissolved in the minimum amount of boiling water and acidified to pH 3 using IN HCl. The solution was cooled to room temperature and left to crystallize overnight. The white solid was removed by filtration and recrystallized from water. Yield = 15%. m.p. = 206-209°C. 1H NMR, 200 MHz, (DMSO) δ: 1.2 (d, 3H, J= 6.4Hz), 4.2 (m, IH), 5.9 (d, IH, J=9.6 Hz), 8.1 (s, IH), 11.0 (s, IH).

General Procedure for the Synthesis of 3-Amino-l -Benzyl- Dihydrouracils: General Procedure for the Michael Addition of Benzyl Amine to Methyl Acrylate or Methyl Crotonate:

Addition of benzyl amine to methyl acrylate: Benzylamine, (2.14 mL, 20 mmol) in dry dichloromethane, (50 mL) was added to a solution of methyl acrylate (2.0 mL, 22 mmol) and MgBr₂*OEt (1.55 g, 6 mmol) in dry dichloromethane (50 mL). The reaction was left to stir overnight, and then quenched with water. The organic layer was extracted and dried over Na₂SO₄. Dichloromethane was removed under reduced pressure and the resulting oil, (3.7 g, 96%) yield), used without further purification.

3-Benzylamino-Propionic Acid Methyl Ester: 1H NMR, 200 MHz, (CDC1₃) δ: 2.5 (t, 2H, J= 6.6 Hz), 2.9 (t, 2H, J= 6.6Hz), 3.6 (s, 3H), 3.8 (s, 2H), 7.3 (m, 5H)

3-Benzylamino-Butyric Acid Methyl Ester: Prepared as a pale yellow oil (3.7 g, 89% yield) by the method described above using benzylamine, (2.14 mL, 20 mmol), methyl crotonate, (2.3 mL, 22 mmol) and magnesium bromide diethyl etherate (1.55 g, 6.0 mmol). 1H NMR, 300MHz, CDC1₃: δ 1.1 (d, 3H, J= 6.3 Hz), δ 2.3 (dd, IH, J_AB= 15 Hz, J_AX= 6.3 Hz), δ 2.4 (dd, IH, J_BA= 15 Hz, J_BX= 6.8 Hz), δ 3.1 (m, IH), δ 3.6 (s, 2H), δ 3.7 (s, 3H), δ 7.3 (m, 5H).

General Procedure for the Synthesis of the 3- Amino Substituted Dihydrouracils:

3-amino-l-benzyl-5,6-dihydropyrimidine-2,4-dione: t-Butyl carbazate, (1.54 g, 7.1 mmol) in 35 mL of 1,4-dioxane was added via a dropping funnel to a solution of carbonyl diimidazole (1.54 g, 8.6 mmol) in 35 mL of 1,4-dioxane. The solution was left to stir for three hours at room temperature. N-Methyl-β-alanine-methyl ester (1.36 g, 7.1 mmol) was added and the reaction heated to 100°C overnight. The solvent was removed under reduced pressure. The resulting yellow oil was dissolved in dichloromethane and washed with water and 0. IN HCl. The organic layer was dried over Νa₂SO₄and solvent removed under reduced pressure. The resulting white foam was dissolved in a solution of 4M HCl in dioxane and stirred at room temperature for five hours. The solvent was removed under reduced pressure and the resulting white foam dissolved in water. An excess of NaHCO₃ was added, and was then extracted with dichloromethane. The solvent was removed under reduced pressure and the resulting oil purified by column chromatography, followed by recrystallization. Prepared as a yellow solid in 4% yield by the method described above. m.p= 58-60°C. IR λ (cm^"1): 3319, 3060, 1706, 1666; Η NMR (CDC1₃) δ: 2.7 (t, 2H, J= 6.8 Hz), 3.3 (t, 2H, J= 6.8 Hz), 4.6 (s, 2H), 7.3 (m, 5H); ¹³C NMR: 31.8, 40.7, 52.4, 128.8, 129.6; Mass Spec. (ES⁺) = 220.1. High Res. C_nH₁₃N₃O₂ requires = 219.100777, found = 219.101084.

3-Amino-l-Benzyl-6-Methyl-5,6-Dihydropyrimidine-2,4-Dione: Prepared as a yellow oil in 12% yield by the method described above. 1H NMR (CDC1₃) δ: 1.15 (d, 3H, J= 6.6 Hz), 2.5 ( dd, IH, J_AB= 16.8 Hz, J_AX= 2.4Hz), 2.8 (dd, IH, J_BA= 16.8 Hz, J_BX= 6.2Hz), 3.5 (m, IH), 4.105 (d, IH, J=15 Hz), 4.7 (s, 2H), 5.1 (d, IH, J= 15 Hz), 7.3 (m, 5H); ¹³C NMR: 18.4, 38.5, 46.9, 50.3, 54.194, 128.5, 128.6, 129.5, 137.4, 153.0, 166.6. Mass Spec. (Tit) = 233.27, high res. C₁₂H₁₅N₃O₂ requires - 233.116427, found = 233.116701. General Procedure for the Synthesis of 6-Aryl-Substituted Dihydrouracils: Method A:

6-phenyl-5,6-dihydropyrimidine-2,4-dione: Cinnamic acid (500 mg, 3.4 mmol) was combined with urea (1.0 g, 0.017 mol) and heated to 190°C for 2 hours. The resulting yellow oil was then taken up in water and refluxed for 1.5 hours. The reaction was left to cool to room temperature and the solid cinnamoyl urea removed by filtration. The filtrate was extracted with ether, and the organic layer dried with Na₂SO₄. Solvent was removed under reduced pressure and the product purified by recrystallization.

General Procedure for the Synthesis of 6-Aryl-Substituted Dihydrouracils: Method B: 6-[3-(3,4-Dichlorophenoxy)-Phenyl]-5,6-dihydropyrimidine-2,4-dione: 3-(3,4- dichlorophenoxy)-cirmamic acid (4.7 g, 0.015 mol) and urea (4.6 g, 0.076 mol) were combined and heated to 190°C for 2 hours. The resulting amber-colored oil was dissolved in hot ethanol and refluxed for 1 hour. The reaction was cooled to room temperature and a white solid collected by filtration. This was then purified by recrystallization from methanol. 6-Phenyl-5,6-Dihydropyrimidine-2,4-Dione: Prepared as a white solid in 4% yield as described in method A. m.p.= 218°C. 1H NMR (CD₃OD) δ: 2.8 (dd, IH, J_AB= 16.8 Hz, J_AX= 8.1 Hz), 2.9 (dd, IH, J_BX= 5.6 Hz, J_BA= 16.8 Hz), 4.8 (m, IH), 7.4 (m, IH), 8.0 (s, IH), 10.2 (s, IH)

6-meta-Tolyl-5,6-Dihydropyrimidine-2,4-Dione: Prepared as a white solid in 5% yield as described in method A from 3-methyl cinnamic acid (500 mg, 3.1 mmol), and urea (931 mg, 0.0156 mol). m.p.= 201-203°C. IR λ (cm^"1): 3202, 3087, 2909, 1738, 1696, 1450; 1H NMR (DMSO) δ: 2.3 (s, 3H), 2.6 (dd, IH, J_AB= 16.4 Hz, J_AX= 6.6 Hz), 2.8 (dd, IH, J_BA= 16.4 Hz, J_BX= 5.8 Hz), 3.4 (m, IH), 7.1-7.3 (m, 4H); ¹³C NMR,: 19.7, 22.2, 39.4, 51.2, 57.1, 124.2, 127.8, 129.4, 129.6, 138.8, 142.3, 154.9, 171.0. Mass Spec. (Er> 204.1, high res. CπHι₂N₂O₂ requires 204.089878, found = 204.089993.

6-(4-Methoxyphenyl)-5,6-Dihydropyrimidine-2,4-Dione: Prepared as a white solid in 5% yield as described in method A from 4-methoxy cinnamic acid (264 mg, 1.48 mmol), and urea (445 mg, 7.4 mmol). m.p. = 231-232°C. 1H NMR (DMSO) δ: 2.6 (dd, IH, J_AB= 24.4 Hz,

8.4 Hz), 3.4 (m, IH), 3.7 (s, 3H), 6.9 (d, 2H, J= 13 Hz), 7.2 (d, 2H, J=13 Hz), 7.9 (s, IH), 10.1 (s, IH). 6-(4-Methoxy-3-Methyl-Phenyl)-5,6-Dihydropyrimidine-2,4-Dione: Prepared as a white solid in 8% yield as described in method A from 3-methyl-4-methoxy cinnamic acid (5g, 0.028 mol), and urea (8.4 g, 0.14 mol). m.p. = 201-203°C. IR λ (cm^"1): 3227, 3081, 2906, 2834, 1702, 1613, 1509, 1468; Η NMR (DMSO) δ: 2.2 (s, 3H), 2.6 (dd, IH, J_AB= 20.1 Hz, J_AX= 8.1 Hz), 2.8 (dd, 1 H, J_AB= 20.1 Hz, J_BX= 6.3 Hz), 3.8 (s, 3H), 4.6 (m,lH), 7.0 (m, 3H), 7.9 (s, IH), 10.1 (s, IH); ¹³C NMR: 17.5, 39.3, 51.0, 55.1, 111.3, 125.2, 126.4, 129.5, 133.4, 154.6, 157.6, 170.9; Mass Spec (Ef)233.8 = 233.8, high res. Cι₂Hι₄N₂O₃ requires 234.100442, found 234.101209.

6-[3-(3,4-Dichlorophenoxy)-Phenyl]-5, 6-Dihydropyrimidine-2,4-Dione: Prepared as a white solid in 14% yield as described in method B from 3,4-dichlorophenoxy cinnamic acid (4.68 g, 0.015 mol), and urea (4.55 g, 0.076 mol). m.p.= 221-222°C. IR λ (cm^"1): 3432, 3209, 1710, 1577, 1465. 1H NMR, 200 MHz, (DMSO) δ: 2.7 (dd, IH, J^= 7.2 Hz, J_AB= 16.2 Hz), 2.9 (dd, IH, J_BX= 5.8 Hz, J_BA= 16.2 Hz), 4.7 (m, IH), 7-7.7 (m, 7H), 8.1 (s, IH), 10.2 (s, IH); ¹³C NMR: 38.8, 50.7, 118.0, 119.3, 119.5, 121.1, 123.0, 131.4, 132.5, 132.9, 144.6, 154.6, 156.5, 157.1, 170.6; Mass Spec. (Ef) = 350.2; high res.Cι₆H₁₂Cl₂N₂O₃ requires = 350.022498, found 350.023188.

6-[3-(4-Chlorophenoxy)-Phenyl]-5,6-Dihydropyrimidine-2,4-Dione: Prepared as a white solid in 8% yield as described in method B from 3 -chlorophenoxy cinnamic acid (4.44 g, 0.016 mol), and urea (4.80 g, 0.08 mol). m.p= 206-206°C. IR λ (cm^"1): 3194, 3082, 1739, 1695, 1484, 1254; 1H NMR (DMSO) δ: 2.6 (dd, IH, J_AB= 16.1, J_AX= 7.1), 2.8 (dd, IH, J_BA= 16.1, J_BX= 5.6), 4.7 (m, IH), 6.9-7.4 (m, 8H), 8.0 (s, IH), 10.2 (s, IH); ¹³C NMR: 38.9, 49.5, 50.7, 117.4, 118.8, 121.1, 122.5, 128.1, 130.1, 131.3, 144.5, 154.6, 156.3, 157.2, 170.6; Mass Spec. (Ef) = 316.2, high res. Cι₆Hι₃N₂O₃, required = 316.061470, found = 316.062493.

6-(4-Nitro-Phenyl)-5,6-Dihydropyrimidine-2,4-Dione: 6-Phenyl-dihydro- pyrimidine-2,4-dione, (6), (284 mg, 1.4 mmol) was dissolved in 6 mL of a 1:1 (v) solution of HNO₃ and H SO and stirred at room temperature for 30 minutes. The reaction mixture was then poured over ice and a yellow precipitate collected by filtration and purified by recrystallization from 2:1 ethanokether. Yield = 40%. m.p. = 253-255°C. 1H NMR (DMSO) δ: 2.7 (dd, 1 H, J_AX = 6.9 Hz, J_AB = 16.5 Hz), 2.9 (dd, IH, J_BX = 5.7 Hz, J_BA= 16.5 Hz), 4.9 (m, IH), 7.7 (m, 2H), 8.1 (s, IH), 8.3 (m, 2 H), δ 10.3 (s, IH). 3-Methyl-4-Methoxy Cinnamic Acid: 3-Methyl-4-methoxy benzaldehyde, (1.95 mL, 0.013 mol), malonic acid (1.35 g 0.013 mol) were combined with ammonium acetate (2.0 g, 0.026mol) in dry ethanol, then refluxed under argon for 6 hours. The solid β-amino acid was collected by filtration and the filtrate was evaporated to dryness under reduced pressure. The resulting yellow solid was recrystallized first from water, then ethanol. Yield= 18%. ^!H NMR, 200 MHz, (DMSO) δ: 2.2 (s, 3H), 3.8 (s, 3H), 6.4 (d, IH, J= 16.2 Hz), 7.0 (d, IH, J = 8.1 Hz), 7.5 (m, 3H).

3-(3,4-dichlorophenoxy)-cinnamic acid: 3-(3,4-Dichlorophenoxy)benzaldehyde, (3.7 mL, 0.019 mol), and malonic acid (9.78 g, 0.094 mol) and morpholine (0.33 mL, 3.8 mmol) were heated in dry pyridine at 60°C for 8 hours. The reaction was then stirred at room temperature for another 48 hours. The reaction mixture was then poured over a solution of 1% aqueous HCl and stirred at 0°C for 1.5 hours. The solid was collected by filtration and purified by recrystallization from ethanol.

3-(3,4-Dichloro-Phenoxy)-CinnamicAcid: Yield = 80%. m.p.=158-160°C. 1H NMR (DMSO) δ: 6.6 (d, IH, J= 14.1 Hz), 7.0-7.6 (m, 9H); ¹³C NMR: 119.5, 119.6, 121.2, 121.4, 121.7, 126.3, 131.6, 132.5, 132.9, 137.5, 143.8, 156.9, 157.1, 168.3.

3-(3-Chloro-Phenoxy)-Cinnamic Acid: Prepared as a white solid in 83% yield as described above using 3-(4-chlorophenoxy)-benzaldehyde, (4.1 mL, 0.02 mol), malonic acid, (11.2 g, 0.011 mol) and morpholine (2.9 mL, 4 mmol). m.p. = 162-164°C. Η NMR, 300 MHz, DMSO: δ 6.5 (d, IH, J= 15.9 Hz), δ 7.0 ( d, 3H, J= 8.1 Hz), δ 7.4 (m, 5H), δ 7.6 (d, lH, J= 15.9 Hz).

Synthetic Route to Compound 16-25 (as shown in Table 1).

The first synthetic step to produce the starting materials can be used to produce dihydrouracil analogs with substitutions at the 5 and 6 position.

Step l

(1) (2) (3)

- R = H, Br, Cl, methyl, ethyl, propyl, substituted or unsubstituted phenyl (e.g., NO₂, Br, Cl, CH₃), substituted or unsubstituted benzyl (e.g., NO₂, Br, Cl, CH₃), etc. (See substitution selection shown above for Formula I)

Step 2

Cl

(5) - R'= H, Br, Cl, ethyl, ethyl, propyl, substituted or unsubstituted phenyl (e.g., NO₂, Br, Cl, CH₃), substituted or unsubstituted benzyl (e.g., NO₂, Br, Cl, CH₃), etc. (See substitution selection shown above for Formula I).

An alternate route uses a Grignard type reaction (presented below). Again using the product obtained from the first synthetic step, as well as a similar work up as Step 2.

Biolosical Testing

Potential therapeutic compounds can be tested in a variety of seizure models. These models include the pilocarpine induced-seizures (PIS) model, the spontaneous recurrent seizure (SRS) model, maximal electroshock induced-seizures (MES), the subcutaneous pentylenetetrazole induced-seizures (PTZ) model and the hippocampal kindling seizure model. Many of test compounds PI - P 43 showed some activity in at least one of these assays.

Pilocarpine induced-seizure (PIS) model

A seizure model is performed using adult male Sprague-Dawley rats in accordance with the guidelines of the Canada Council on Animal Care and under the supervision of the Queen's University Animal Ethics Committee. This test procedure was adopted from previous work by Turski et al. (1984) Brain Res. 311:131. The test compounds are administered at lOOmg/kg by intraperitoneal (i.p.) injection. Seizures are induced 20 minutes afterwards by i.p. administration of pilocarpine hydrochloride (350 mg/kg). Protection is defined as the absence of clonic spasms over a 30 minute observation period after pilocarpine administration. Spontaneous recurrent seizure (SRS) model

The "spontaneous recurrent seizures" (SRS) model of epilepsy is used to evaluate candidate compounds in a model for Phase 1 epileptogenesis (see, e.g. , Mello, E. et al. , Epilepsia (1993) 34:985; Cavalheiro, J. et al, Epilepsia (1991) 32:778). In the SRS model, an adult male Sprague-Dawley rat (c. 260 g) is given kainic acid by injection (380 mg/kg i.p.). Within 25 minutes, the animal enters status epilepticus, which typically lasts for 15-20 hours (although about 10%o of animals die at this stage). The rat is allowed to spontaneously recover and is given food and water ad lib. and maintained on a 12 hour/ 12 hour light/dusk cycle. Beginning on about day 13-15, the rats develop spontaneous recurrent seizures, which occur at the rate of about 4-5 per week. The rats are videotaped 8 hours per day, and the videotapes are reviewed for behavioral seizures (including head nodding, forelimb clonus, and rearing), which are counted. The animals are watched for three months, permitting evaluation of a sufficient number of seizures. An experimental compound for evaluation can be administered at either of two times: Time 1, on Day 1, after the cessation of status epilepticus but before the onset of SRS; or Time 2, on Day 30, when the rats have been experiencing SRS for about two weeks. Administration of the candidate compound at Time 1 permits evaluation for anti-epileptogenic properties (ability to prevent the onset of seizures); administration of compounds at Time 2 permits evaluation of drugs as anti-ictogenics with the ability to suppress established seizures.

As a reference, the standard anticonvulsant phenytoin can be administered (20 mg/kg/day i.v. for 10 day) at either Time 1 or Time 2.

Maximal electroshock induced-seizure (MES) model For the maximal electroshock seizure test (MES), corneal electrodes primed with a drop of electrolyte solution (0.9% NaCl) are applied to the eyes of the animal and an electrical stimulus (50 mA for mice, 150 mA for rats; 60 Hz) is delivered for 0.2 second at the time of the peak effect of the test compound. The animals are restrained by hand and are released at the moment of stimulation in order to permit observation of the seizure. Abolition of hind- leg tonic-extensor component (hind-leg tonic extension does not exceed a 90° angle to the plane of the body) indicates that the compound prevents MES-induced seizure spread.

Subcutaneous pentylenetetrazole induced-seizure (PTZ) model

In the subcutaneous pentylenetetrazole (PTZ)-induced seizure model, seizures are induced 0.5 and 4 hrs after test compound administration by i.p. injection of PTZ (85mg/kg in mice and 70 mg/kg in rats). Protection is defined as the inhibition of clonic spasms over a 30 min observation period.

Hippocampal kindlins seizure model

This model is particularly useful as it not only provides an experimental model of seizures, but also offers a means of studying the complex brain networks that may contribute to the spread and generalization of seizures from the focus. Biological testing using hippocampal kindling seizure model follows the Lothman procedure (Lothman, et al. , Epilepsy Res., 1988, 2:366) or the Silver procedure (Silver, et al, Ann. Neurol. (1991)

29:356). See also, Lothman, et al., Brain Res., 1994, 649:71, and Racine, et al., Clin.

Neurophysiol., 1972, 32:281.

Neurotoxicity screen Preliminary neurotoxicity induced by the test compound may be characterized by neurologic abnormalities and poor performance in given tasks. For instance, the neurologic deficit may be indicated by the inability to maintain equilibrium for one minute in each of three trials on a knurled rod rotating at 6 rpm. Other tests for neurotoxicity include the rotorod ataxia test, positional sense test, and gait and stance test. In the positional sense test, one hind leg is gently lowered over the edge of a table. The animal quickly reacts by returning the leg to the normal position. Failure to do so rapidly indicates a neurologic deficit. In the gait and stance test, the neurologic deficit is indicated by a circular or zigzag gait, ataxia, and/or other abnormal events that may include abnormal spread of legs, body posture, tremor, hyperactivity, lack of exploratory behavior, somnolence, stupor, and catalepsy. Initial testing (PTZ, MES, Neurotoxicity) was carried out in the specified number of animals at doses of 30, 100, 300 mg/kg (Table 3), at interval times of 30 minutes and 4 hours after administering the test compound.

Biological testins results

In vivo biological test results are given in Tables 2 and 3. Compounds not tested are shown as blank. Compounds 31, 32, 29, 9, 2, 5, 10, 11, 13 show activity in the pilocarpine assay (Table 2). Compounds 29 and 13 are active in the MES assay (Table 3); 29 and 12 are active in PTZ (Table 3); 30, 5, 10 and 12 showed no toxicity; 29 and 13 showed moderate toxicity at higher doses (Table 3).

For anti epileptic screening: number of animals protected over number of animals tested is shown. For toxicity screening: number of animals showing toxicity symptoms over number of animals tested is shown.

The results obtained in the in vivo assays clearly illustrate the anti-ictogenic activity of this dihydrouracil family of compounds. Compounds 31, 29, 9, 5, 10, 11, 13 presented moderate activity in the pilocarpine assay with 2 of the 4 treated animals being protected from seizure activity. Compounds 32 and 2 presented strong activity with 3 of 4 animals treated being protected.

In parallel, results of MES and PTZ assays corroborated the strong anticonvulsive activity of compound 29, as the compound provided protection at all doses tested (30, 100 and 300 mg/kg) in the MES assay and at 100 and 300 mg/kg in the PTZ assay. Compound 13 also yielded positive results in the MES assay as it provided protection at 100 and 300 mg/kg. The PTZ assay demonstrated protective activity for compound 12 at 300 mg/kg. EQUIVALENTS

Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, numerous equivalents to the specific procedures described herein.

Such equivalents are considered to be within the scope of the present invention and are covered by the following claims. The contents of all references, issued patents, and published patent applications cited throughout this application are hereby incorporated by reference. The appropriate components, processes, and methods of those patents, applications and other documents may be selected for the present invention and embodiments thereof.

Claims

CLAIMS What is claimed is:

1. An anti-ictogenic or anti-epileptogenic compound of the formula

wherein

R1, R2, R3_? R4_} R5₅ and R6 _are independently a hydrogen atom, a substituted or unsubstituted straight or branched alkyl, substituted or unsubstituted straight or branched alkoxy, substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heterocyclic, substituted or unsubstituted carbocyclic, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted aryloxyalkyl, substituted or unsubstituted arylacetamidoyl, substituted or unsubstituted alkylaryl, substituted or unsubstituted heteroaralkyl, substituted or unsubstituted alkylcarbonyl, substituted or unsubstituted arylcarbonyl, substituted or unsubstituted heteroarylcarbonoyl, or substituted or unsubstituted heteroaryl group, (CR'R")o-3NR'R" (including NH₂ and dialkylamino), (CR'R")₀-3CN (including CN), (CR'R")₀-3NO2 (including NO2), halogen, (CR'R")₀. ₃C(halogen)₃, (CR'R")o_3CH(halogen)₂, (CR'R")₀.3CH₂(halogen), (CR'R")₀. ₃CONR'R", (CR'R")o.3S(O)ι_₂NR'R", (CR'R")₀-3CHO, (CR'R")₀. ₃O(CR'R")o_₃H, (CR'R")₀-₃S(O)o-2R\ (CR'R")θ-3θ(CR'R")₀-₃H, (CR'R")₀.

3COR', (CR'R")₀.3CO₂R' (including CO₂H), or (CR'R")₀-3OR' group; wherein R' and R" are each independently hydrogen, a C1-C5 alkyl, C2-C5 alkenyl, C2-C5 alkynyl, or aryl group, or R' and R" taken together are a benzylidene group or a - (CH2)_nO(CH2)_n- (where each n is 1, 2, or 3) group; or pharmaceutically acceptable salts or esters thereof.

2. The compound of claim 1, wherein

R¹ is H or NH₂;

R2 or R5 is hydrogen, halogen, substituted or unsubstituted phenyl, nitro, substituted or unsubstituted alkoxy, or substituted or unsubstituted alkyl; R3 or R6 is hydrogen, substituted or unsubstituted aryl, substituted or unsubstituted alkoxy, or substituted or unsubstituted alkyl; and

R4 is hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted phenyl; provided that at least one of R^, R3, R4, R5_{? or} R6 \_{S no}t _a hydrogen; and pharmaceutically acceptable salts or esters thereof.

3. The compound of claim 1, wherein said compound is selected from the group consisting of the compounds recited in Table 1 hereof, any other novel chemical compound recited herein, and pharmaceutically acceptable salts or esters thereof.

4. A pharmaceutical composition comprising an amount of a compound of any one of claims 1 - 3, effective to treat or prevent ictogenesis or epileptogenesis in a subject in need thereof, and a pharmaceutically acceptable carrier.

5. Use of a pharmaceutical composition comprising a compound of any one of claims 1 - 3 in the treatment or prevention of ictogenesis or epileptogenesis.

6. Use of a compound of any one of claims 1 - 3 in the preparation of a medicament for use in the treatment or prevention of ictogenesis or epileptogenesis.

7. A method for preventing or treating epileptogenesis or ictogenesis, comprising administering to a subject in need thereof an effective amount of an anti-epileptogenic or anti-ictogenic compound of the formula

wherein R*, R^, R3, R4, R5_{? an}d R6 ^Q independently a hydrogen atom, a substituted or unsubstituted straight or branched alkyl, substituted or unsubstituted straight or branched alkoxy, substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heterocyclic, substituted or unsubstituted carbocyclic, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted aryloxyalkyl, substituted or unsubstituted arylacetamidoyl, substituted or unsubstituted alkylaryl, substituted or unsubstituted heteroaralkyl, substituted or unsubstituted alkylcarbonyl, substituted or unsubstituted arylcarbonyl, substituted or unsubstituted heteroarylcarbonoyl, or substituted or unsubstituted heteroaryl group, (CR'R")₀-3NR'R" (including NH₂ and dialkylamino), (CR'R")₀_3CN (including CN), (CR'R")₀-3NO₂ (including NO2), halogen, (CR'R")₀. ₃C(halogen)₃, (CR'R")₀.3CH(halogen)₂, (CR'R")θ-3CH₂(halogen), (CR'R")₀. ₃CONR'R", (CR'R")o-3S(O)ι_₂NR'R", (CR'R")₀-3CHO, (CR'R")₀. ₃O(CR'R")o-₃H, (CR'R")o-₃S(O)o-2R\ (CR'R")₀.₃O(CR'R")o.3H, (CR'R")₀.

3COR', (CR'R")o.3CO₂R' (including CO₂H), or (CR'R")₀-3OR' group; wherein R' and R" are each independently hydrogen, a C1 -C5 alkyl, C2-C5 alkenyl, C2-C5 alkynyl, or aryl group, or R' and R" taken together are a benzylidene group or a - (CH2)_nO(CH2)_n- (where each n is 1, 2, or 3) group; or pharmaceutically acceptable salts or esters thereof.

8. A method for preventing or treating epileptogenesis or ictogenesis according to claim 7, wherein

R¹ is H or NH₂;

R2 or R5 is hydrogen, halogen, substituted or unsubstituted phenyl, nitro, substituted or unsubstituted alkoxy, or substituted or unsubstituted alkyl;

R3 or R6 is hydrogen, substituted or unsubstituted aryl, substituted or unsubstituted alkoxy, or substituted or unsubstituted alkyl; and

R4 is hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted phenyl; provided that at least one of R², R³, R4 R5_{? or} R6 J_{S no a} hydrogen; and pharmaceutically acceptable salts or esters thereof.

9. A method for preventing or treating epileptogenesis or ictogenesis according to claim 7, wherein said compound is selected from the group consisting of the compounds recited in Table 1 hereof, any other novel chemical compound recited herein, and pharmaceutically acceptable salts or esters thereof.

10. A method for inhibiting epileptogenesis in a subject, comprising administering to a subject an effective amount of an anti-epileptogenic agent, such that said epileptogenesis in said subject is inhibited, wherein said anti-epileptogenic agent is a compound of Formula I as defined in claim 1, or a pharmaceutically acceptable salt, ester, N-substituted analog, or prodrug thereof.

11. A method for treating a subject suffering from an epileptogenesis-associated condition, comprising administering to said subject an effective amount of an anti- epileptogenic agent, such that said subject is treated wherein said anti-epileptogenic agent is a compound of Formula I as defined in claim 1, or a pharmaceutically acceptable salt, ester, N-substituted analog, or prodrug thereof.

12. A method for preventing or treating convulsions in a subject comprising administering to said subject an effective amount of an anti-epileptogenic agent, such that said subject is treated, wherein said anti-epileptogenic agent is a compound of Formula I as defined in claim 1 , or a pharmaceutically acceptable salt, ester, N-substituted analog, or prodrug thereof.

13. The method of any claim herein, wherein said subject is suffering from epilepsy, traumatic brain injury (TBI), head trauma, neurosurgery, pain, stroke, anxiety, schizophrenia, multiple sclerosis, amyotrophic lateral sclerosis, psychoses, cerebral ischemia, Huntington's chorea, motor neuron disease, Alzheimer's disease, or dementia.

14. The method of any one of the claims 10, 11, and 12, wherein said anti-epileptogenic agent modulates GAT-1 or GAT-2.

15. The method of any one of the claims 10, 11, and 12, wherein said anti-epileptogenic agent modulates GAT-3.

16. The method of any one of the claims 10, 11, and 12, wherein said anti-epileptogenic agent inhibits the uptake of synaptic GABA.

17. The method of any one of the claims 10, 11, and 12, wherein said anti-epileptogenic agent is a glutamatergic excitation modulator.

18. The method of any one of the claims 10, 11, and 12, wherein said anti-epileptogenic agent is a glutamatergic excitation inhibitor.

19. The method of any one of the claims 10, 11, and 12, wherein said anti-epileptogenic agent interacts with the NMDA receptor.

20. The method of any one of the claims 10, 11, and 12, wherein said anti-epileptogenic agent is capable of crossing the blood brain barrier.

21. The method of any one of the claims 10, 11, and 12, wherein said anti-epileptogenic agent has a pharmaceutically acceptable neurotoxicity.

22. The method of any of the foregoing claims, wherein said epileptogenesis-associated condition is epilepsy, traumatic brain injury (TBI), head trauma, neurosurgery, pain, stroke, anxiety, schizophrenia, multiple sclerosis, amyotrophic lateral sclerosis, psychoses, cerebral ischemia, Huntington's chorea, motor neuron disease, Alzheimer's disease, or dementia.

23. The method of claim 22, wherein said epileptogenesis-associated condition is epilepsy.

24. A pharmaceutical composition, comprising a therapeutically effective amount of an anti-epileptogenic agent and a pharmaceutical acceptable carrier, wherein said anti- epileptogenic agent is selected from the group consisting of compounds listed in Table 1, and pharmaceutically acceptable salts or esters, N-substituted analogs, and prodrugs thereof.

25. The pharmaceutical composition for treating an epileptogenesis-associated state comprising an effective amount of a compound of the Formula of any one of the claims 10, 11, and 12, wherein said effective amount is effective to treat an epileptogenesis-associated state.

26. The pharmaceutical composition of claim 25, wherein said epileptogenesis-associated state is epilepsy, traumatic brain injury (TBI), head trauma, neurosurgery, pain, stroke, anxiety, schizophrenia, multiple sclerosis, amyotrophic lateral sclerosis, psychoses, cerebral ischemia, Huntington's chorea, motor neuron disease, Alzheimer's disease, or dementia.

27. The pharmaceutical composition of claim 26, wherein said epileptogenesis-associated state is epilepsy.

28. The method of any of the foregoing claims, wherein said anti-epileptogenic agent inhibits or modulates GABA transaminase.

29. The method of claim 7 or 9, wherein the compound selected provides both anti- ictogenic and anti-epileptogenic protection.

30. The method of claim 29, wherein at least some of the anti-ictogenic or anti- epileptogenic protection is provided in vivo by a metabolite of the administered compound.

31. The pharmaceutical composition of claim 26, wherein said epileptogenesis-associated state is TBI.