EP1385831A2 - Composes de pyrimidine en tant qu'agents anti-ictogeniques et/ou anti-epileptiques - Google Patents

Composes de pyrimidine en tant qu'agents anti-ictogeniques et/ou anti-epileptiques

Info

Publication number
EP1385831A2
EP1385831A2 EP02717913A EP02717913A EP1385831A2 EP 1385831 A2 EP1385831 A2 EP 1385831A2 EP 02717913 A EP02717913 A EP 02717913A EP 02717913 A EP02717913 A EP 02717913A EP 1385831 A2 EP1385831 A2 EP 1385831A2
Authority
EP
European Patent Office
Prior art keywords
compound
subject
pharmaceutically acceptable
hydrogen
compounds
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP02717913A
Other languages
German (de)
English (en)
Inventor
Donald F. Weaver
Buhendwa Musole Guillain
John R. Carran
Kathryn Jones
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Queens University at Kingston
Original Assignee
Queens University at Kingston
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Queens University at Kingston filed Critical Queens University at Kingston
Publication of EP1385831A2 publication Critical patent/EP1385831A2/fr
Withdrawn legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
    • C07D239/52—Two oxygen atoms
    • C07D239/54—Two oxygen atoms as doubly bound oxygen atoms or as unsubstituted hydroxy radicals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/08—Antiepileptics; Anticonvulsants
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
    • C07D239/52—Two oxygen atoms
    • C07D239/54—Two oxygen atoms as doubly bound oxygen atoms or as unsubstituted hydroxy radicals
    • C07D239/545—Two oxygen atoms as doubly bound oxygen atoms or as unsubstituted hydroxy radicals with other hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/553—Two oxygen atoms as doubly bound oxygen atoms or as unsubstituted hydroxy radicals with other hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms with halogen atoms or nitro radicals directly attached to ring carbon atoms, e.g. fluorouracil
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
    • C07D239/52—Two oxygen atoms
    • C07D239/54—Two oxygen atoms as doubly bound oxygen atoms or as unsubstituted hydroxy radicals
    • C07D239/545—Two oxygen atoms as doubly bound oxygen atoms or as unsubstituted hydroxy radicals with other hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/557—Two oxygen atoms as doubly bound oxygen atoms or as unsubstituted hydroxy radicals with other hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms, e.g. orotic acid
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
    • C07D239/72—Quinazolines; Hydrogenated quinazolines
    • C07D239/95—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in positions 2 and 4
    • C07D239/96—Two oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D473/00—Heterocyclic compounds containing purine ring systems
    • C07D473/02—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6
    • C07D473/04—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two oxygen atoms
    • C07D473/06—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two oxygen atoms with radicals containing only hydrogen and carbon atoms, attached in position 1 or 3
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems

Definitions

  • Epilepsy is a serious neurological condition, associated with seizures, that affects hundreds of thousands of people worldwide.
  • a seizure results from a sudden electrical discharge from a collection of neurons in the brain.
  • the resulting nerve cell activity is manifested by symptoms such as uncontrollable movements.
  • a seizure is a single discrete clinical event caused by an excessive electrical discharge from a collection of neurons through a process termed "ictogenesis.” As such, a seizure is merely the symptom of epilepsy.
  • Epilepsy is a dynamic and often progressive process characterized by an underlying sequence of pathological transformations whereby normal brain is altered, becoming susceptible to recurrent seizures through a process termed "epileptogenesis.” While it is believed that ictogenesis and epileptogenesis have certain biochemical pathways in common, the two processes are not identical. Ictogenesis (the initiation and propagation of a seizure in time and space) is a rapid and definitive electrical/chemical event occurring over seconds or minutes. Epileptogenesis (the gradual process whereby normal brain is transformed into a state susceptible to spontaneous, episodic, time-limited, recurrent seizures, through the initiation and maturation of an "epileptogenic focus”) is a slow biochemical and/or histological process which generally occurs over months to years.
  • 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 and/or severity. While the processes involved in epileptogenesis have not been definitively identified, some researchers believe that upregulation of excitatory coupling between neurons, mediated by N-methyl-D-aspartate (NMD A) receptors, is involved.
  • N-methyl-D-aspartate (NMD A) receptors is involved.
  • GABA gamma-aniino-butyric acid
  • 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 felbar ⁇ ate, gabapentin, and tiagabine.
  • ⁇ -alanine has been reported to have anticonvulsant activity, as well as NMDA inhibitory activity and GABAergic stimulatory activity, but has not been employed clinically.
  • anticonvulsant agents where the term “anticonvulsant” is synonymous with “anti-seizure” or “anti-ictogenic;” these drugs can suppress seizures by blocking ictogenesis, but it is believed that they do not influence epilepsy because they do not block epileptogenesis.
  • anticonvulsant i.e., through suppression of the convulsions associated with epileptic seizures
  • This invention provides an anti-ictogenic and or anti-epileptogenic compound of the formula (Formula XIV)
  • R 9 is hydrogen, alkyl, alkynyl, hydroxy, halogen, nitro, carboxyl, or,R 9 and R 10 together form a 5- or 6-membered carbocyclic or heterocyclic ring
  • R 10 is hydrogen, alkyl, carboxyl, or R 9 and w together form a 5- or 6-membered carbocyclic or heterocyclic ring
  • R n is hydrogen or alkyl
  • R 12 is hydrogen or alkyl; or pharmaceutically acceptable salts or esters (for example, of a hydroxyl or carboxyl group) thereof.
  • the invention also includes a pharmaceutical composition comprising any of the above compounds in combination with a pharmaceutically acceptable carrier.
  • a pharmaceutically acceptable carrier for example, the invention includes an anti-convulsive pharmaceutical composition including an amount of one or more of the above compounds effective to inhibit a convulsive disorder (e.g., epilepsy) in a subject in need thereof, and a pharmaceutically acceptable carrier.
  • a convulsive disorder e.g., epilepsy
  • this invention features a method of treating or preventing ictogenesis in a subject in need thereof including administering to the subject an amount of one or more of the above compounds to inhibit ictogenesis in the subject so that ictogenesis is treated or prevented in the subject.
  • this invention features a method of treating or preventing epileptogenesis in a subject in need thereof including administering to the subject an amount of one or more of the above compounds to inhibit epileptogenesis in the subject so that epileptogenesis is treated or prevented in the subject.
  • this invention provides a kit-for treating or preventing ictogenesis in a subject including one of the above compounds, and instructions for a ⁇ n-u istering a therapeutically effective amount of a compound to the subject so that ictogenesis is treated or prevented in the subject.
  • this invention provides a kit for treating or preventing epileptogenesis in a subject including one of the above compounds, and instructions for administering a therapeutically effective amount of a compound to the subject so that 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 to the NMDA 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 incl uding administering to the subj ect an amount of one of the above compounds so that seizures are treated or prevented in the subject.
  • Figure 1 depicts exemplary pyrimidine and d ⁇ hydropyrimidine compounds useful in the methods of the invention and their putative metabolic conversion to ⁇ -amino acids.
  • Figure 1 depicts exemplary synthetic schemes for preparing pyrimidine and dihydropyrimidine compounds of the invention.
  • This invention pertains to methods and agents useful for the treatment of epilepsy and convulsive 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 compounds of the invention.
  • 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.
  • 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.
  • 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.
  • convulsive disorder includes disorders 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.
  • inhibition of epileptogenesis includes preventing, slowing, halting, or reversing the process of epileptogenesis.
  • anti-epileptogenic agent includes agents which are capable of inhibiting epileptogenesis when the agent is administered to a subject.
  • anticonvulsant agent includes agents capable of inhibiting (e.g., preventing, slowing, halting, or reversing ) ictogenesis when the agent is administered to a subject.
  • pharmacophore is known in the art, and includes molecular moieties capable of exerting a selected biochemical effect, e.g., inhibition of an enzyme, binding to a receptor, chelation of an ion, and the like.
  • a selected pharmacophore can have more than one biochemical effect, e.g., can be an inhibitor of one enzyme and an agonist of a second enzyme.
  • a therapeutic agent can include one or more pharmacophores, which can have the same or different biochemical activities.
  • pharmacophores with similar structures and/or properties may be combined to predict or design an optimized or "average pharmacophore" structure.
  • Such an average pharmacophore structure may provide a more desired level of biological effect than the individual pharmacophores used to create the average structure.
  • anionic group refers to a group that is negatively charged at physiological pH.
  • Preferred anionic groups include carboxylate, sulfate, sulfonate, sulfinate, sulfamate, tetrazolyl, phosphate, phosphonate, phosphinate, or phosphorothioate or functional equivalents thereof.
  • "Functional equivalents" of anionic groups include bioisosteres, e.g., bioisosteres of a carboxylate group. Bioisosteres encompass both classical bioisosteric equivalents and non- classical bioisosteric equivalents. Classical and non-classical bioisosteres are known in the art. See, e.g., Silverman, R.B. The Organic Chemistry of Drug Design and Drug Action, Academic Press, Inc.: San Diego, CA, 1992, pp. 19-23.
  • a particularly preferred anionic group is a carboxylate.
  • ⁇ -amino anionic compound includes compounds having an amino group, such as -NR a R b , where R a and R b may each independently be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, or aryloxycarbonyl, or R a and R b , taken together with the nitrogen atom to which they are attached, form a cyclic moiety having from 3 to 8 atoms in the ring separated from an anionic group by a two-carbon spacer unit.
  • a ⁇ -amino anionic compound can be represented by the substructural formula A-C-C-NR a R b , where A is an anionic group.
  • Preferred ⁇ -amino anionic compounds include ⁇ -amino acids and analogs thereof.
  • the ⁇ -amino anionic compound is not ⁇ -alanine or taurine.
  • subject is known in the art, and refers to a warm-blooded animal, more preferably a mammal, including non-human animals such as rats, mice, cats, dogs, sheep, horses, cattle, in addition to apes, monkeys, and humans. In a preferred embodiment, the subject is a human.
  • the chemical groups of the present invention may be substituted or unsubstituted. Further, unless specifically indicated, the chemical substituents may in turn be substituted or unsubstituted. In addition, multiple substituents may be present on a chemical group or substituent.
  • substituents include alkyl, alkenyl, alkynyl, aryl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxyl, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, formyl, trimethylsilyl, phosphate, phosphonato, phosphinato, cyano, amino (including alkyl amino, dialkylamino, arylamino, diary lamino, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amido, imino, sulfhydryl, alkylthio, arylthi
  • alkyl refers to saturated aliphatic groups, including straight-chain alkyl groups, branched-chain alkyl groups, cycloalkyl, heterocyclyl, cycloalkyl (alicyclic) groups, alkyl substituted cycloalkyl groups, and cycloalkyl substituted alkyl groups.
  • a straight chain or branched chain alkyl has 30 or fewer carbon atoms in its backbone (e.g., C r C 30 for straight chain, C 3 -C 30 for branched chain), and more preferably has 20 or fewer carbon atoms in the backbone.
  • preferred cycloalkyls have from 4-10 carbon atoms in their ring structure, and more preferably have 5, 6 or 7 carbons in the ring structure.
  • alkyl e.g., methyl, ethyl, propyl, butyl, pentyl, hexyl, etc.
  • alkyl include both
  • unsubstituted alkyl and “substituted alkyl”, the latter of which refers to alkyl moieties having substituents replacing a hydrogen on one or more carbons of the hydrocarbon backbone.
  • substituents can include, for example, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, alkoxycarbonyl, 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, alkyl
  • aryl includes 5- and 6-membered single-ring aromatic groups that may include from zero to four heteroatoms, for example, benzene, pyrrole, furan, thiophene, imidazole, oxazole, thiazole, triazole, pyrazole, pyridine, pyrazine, pyridazine and pyrimidine, and the like.
  • Aryl groups also include poly cyclic fused aromatic groups such as naphthyl, quinolyl, indolyl, and the like.
  • aryl groups having heteroatoms in the ring structure may also be referred to as "aryl heterocycles," “heteroaryls” or “heteroaromatics.”
  • the aromatic ring e.g., phenyl, indole, thiophene
  • the aromatic ring can be substituted at one or more ring positions with such substituents as described above, as for example, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, cyano, amino (including alkyl amino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, aryl
  • alkenyl and alkynyl include unsaturated aliphatic groups analogous in length and possible substitution to the alkyls described above, but that contain at least one double or triple bond respectively and at least two adjacent carbon atoms.
  • an "optional single/double bond” is represented by a solid line together with a dashed line, and refers to a covalent linkage between two carbon atoms which can be either a single bond or a double bond of either E- or Z- configuration where appropriate.
  • lower alkyl means an alkyl group as defined above, but having from one to ten carbons, more preferably from one to six carbon atoms in its backbone structure.
  • lower alkenyl and “lower alkynyl” have similar chain lengths (and at least two carbon atoms).
  • Preferred alkyl groups are lower alkyls.
  • heterocyclyl or “heterocyclic group” refer to 3- to 10-membered ring structures, more preferably 4- to 7-membered rings, which ring structures include one or more heteroatoms, e.g., two, three, or four.
  • Heterocyclyl groups include pyrrolidine, oxolane, thiolane, piperidine, piperazine, morpholine, lactones, lactams such as azetidinones and pyrrolidinones, sultams, sultones, and the like.
  • the heterocyclic ring can be substituted at one or more positions with such substituents as described above, including halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, alkoxycarbonyl, 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, sulfonato, sulfamoyl,
  • polycyclyl or “polycyclic group” refer to two or more cyclic rings (e.g., cycloalkyls, cycloalkenyls, cycloalkynyls, aryls and/or heterocyclyls) where 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 can be substituted with such substituents as described above, as for example, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, alkoxycarbonyl, 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, sulfonato, sulfamoyl,
  • heteroatom as used herein means an atom of any element other than carbon or hydrogen. Preferred heteroatoms are nitrogen, oxygen, sulfur and phosphorus.
  • aryl aldehyde refers to a compound represented by the formula Ar-C(O)H, where Ar is an aryl moiety (as described above) and -C(O)H is a formyl or aldehydo group. In a preferred embodiment, the aryl aldehyde is a (substituted or unsubstituted) benzaldehyde. A variety of aryl aldehydes are commercially available, or can be prepared by routine procedures from commercially available precursors.
  • Procedures for the preparation of aryl aldehydes include the Vilsmeier-Haack reaction (See, e.g., Jutz, Adv. Org. Chem. 9, pt. 1, 225-342 (1976)), the Gatterman reaction (Truce, Org. React. 9, 37-72 (1957)), the Gatterman-Koch reaction (Crounse, Org. React. 5, 290-300 (1949)), and the Reimer- Tiemann reaction (Wynberg and Meijer, Org. React. 28, 1-36 (1982)).
  • the structure of some of the compounds of this invention includes asymmetric carbon atoms. It is to be 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 can be obtained in substantially pure form by classical separation techniques and by stereochemically controlled synthesis. That is, unless otherwise stipulated, any chiral carbon center may be of either (R)- or (S)-stereochemistry. Furthermore, alkenes can include either the E- or Z-geometry, where appropriate.
  • the invention provides methods for treating convulsive disorders, including epilepsy.
  • 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.
  • NMDA N- methyl-D-aspartate
  • GAB A gamma-amino-butyric acid
  • Other processes in pathways associated with epileptogenesis include release of nitric oxide (NO), a neurotransmitter implicated in epileptogenesis; release of calcium (Ca 2+ ), which may mediate damage to neurons when released in excess; neurotoxicity due to excess zinc (Zn 2+ ); neurotoxicity due to excess iron (Fe 2+ ); and neurotoxicity due to oxidative cell damage.
  • NO nitric oxide
  • Ca 2+ calcium
  • Zn 2+ neurotoxicity due to excess zinc
  • Fe 2+ neurotoxicity due to excess iron
  • 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.
  • 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; block voltage- gated ion channels; reduce the release of, reduce the free concentration of (e.g., by chelation), or otherwise reduce the epileptogenic effect of cations including Ca 2+ , Zn 2+ , or Fe 2+ ; inhibit oxidative cell damage; or the like.
  • 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.
  • pharmacophores which can modulate a process in a pathway associated with epileptogenesis include:
  • ⁇ inhibitors of NO synthase such as L-arginine and alkylated derivatives thereof;
  • ⁇ antagonists of NMDA receptors such as (R)- ⁇ -amino acids. See, e.g., Leeson, P.D. and Iverson, L.L., J Med. Chem. (1994) 37:4053-4067 for a general review of inhibitors of the NMDA receptor; ⁇ augmenters of endogenous GAB A inhibition such as inactivators of GAB A aminotransferase like gamma-vinyl-GABA. See, e.g., Krogsgaard-Larsen, P., et al, J. Med. Chem.
  • ⁇ chelators of Ca 2+ , Zn 2+ , or Fe 2+ such as EDTA, EGTA, TNTA, 2,2-bipyridine-4,4,- dicarboxylate, enterobactin, porphyrins, crown ethers, and azacrown ethers;
  • antioxidants such as vitamins C, and E; carotenoids such as ⁇ -carotene; butylated phenols, Trolox (a tocopherol analog), selenium; and glutathione.
  • the agent antagonizes an NMDA receptor and augments endogenous GABA inhibition.
  • the agent is administered orally.
  • 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).
  • BBB blood-brain barrier
  • the step of administering to the subject can include administering to the subject a compound which is metabolized to an anti-convulsant and/or anti-epileptogenic compound of the invention.
  • the methods of the invention include the use of prodrugs which are converted in vivo to the therapeutic compounds of the invention.
  • Such prodrugs can be used to alter the biodistribution to allow compounds which would not typically cross the blood-brain barrier to cross the blood-brain barrier, or the pharmacokinetics of the therapeutic compound.
  • an anionic group e.g., a carboxylate group
  • an anionic group can be esterified with an ethyl or a fatty group to yield a carboxylic ester.
  • the carboxylic ester is administered to a subject, the ester can be cleaved, enzymatically or non-enzymatically, to reveal the anionic group.
  • the methods of the invention include administering to the subject a derivative of uracil or an analog thereof (including substituted pyrimidines, UMP and uridine, or analogs thereof).
  • Administration of a uracil compound or metabolite thereof, such as a dihydrouracil or a ⁇ -ureidopropionate can result in the in vivo formation of an active compound of the invention.
  • the methods of the invention may include the step of administering to a subject in need thereof an effective amount of a substituted or unsubstituted uracil, dihydrouracil or ⁇ -ureidopropionate compound, or a derivative or analog thereof (or a pharmaceutically acceptable salt or ester thereof), in an amount effective to treat a convulsive disorder and/or to inhibit epileptogenesis, e.g., by in vivo conversion of the uracil, dihydrouracil or ⁇ -ureidopropionate compound to a ⁇ -amino acid compound effective to treat the convulsive disorder.
  • preferred compounds for administration to a subject include pyrimidines such as substituted uracils which can be converted in vivo to ⁇ -amino anionic compounds.
  • the compound can be represented by the formula (Formula V):
  • R 9 and R 10 may each independently be hydrogen, alkyl (including cycloalkyl, heterocyclyl, and aralkyl), alkenyl, alkynyl, aryl, alkoxy, aryloxy, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aryloxycarbonyl, amino (including unsubstituted and substituted amino), hydroxy, thiol, alkylthiol, nitro, cyano, halogen, carboxyl, alkoxycarbonyloxy, aryloxycarbonyloxy or aminocarbonyl; or R 9 and R 10 , together with the two-carbon unit to which they are attached, are joined to form a carbocyclic or heterocyclic ring having from 4 to 8 members in the ring; and R n is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, alkylcarbonyl, arylcarbonyl, alkoxycarbony
  • the compound can be represented by the formula (Formula Va): where R 9a , R 9b , R 10a , R 10b may each independently be hydrogen, alkyl (including cycloalkyl, heterocyclyl, and aralkyl), alkenyl, alkynyl, aryl, alkoxy, aryloxy, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aryloxycarbonyl, amino (including unsubstituted and substituted amino), hydroxy, thiol, alkylthiol, nitro, cyano, halogen, carboxyl, alkoxycarbonyloxy, aryloxycarbonyloxy or aminocarbonyl; or R 9a and R 9b , together with the two-carbon unit to which they are attached, are joined to form a carbocyclic or heterocyclic ring having from 4 to 8 members in the ring; or R 10a and R 10b , together with the two-carbon unit to
  • a preferred group of compounds according to the invention include
  • R 9 (each selected independently of other R 9 groups, if any), R 11 , and R 12 are defined above.
  • R 9 , R 10 , R 11 , and R 12 are defined above. More preferred are the following compounds
  • R 9 , R 10 , R n , and R 12 are defined above. Still another preferred group of compounds include
  • R 9 (each selected independently of other R 9 groups, if any), R n , and R 12 are defined above.
  • R 9 each selected independently of other R 9 groups, if any
  • R 10 , R 11 , and R 12 are defined above, and including all possible stereoisomers.
  • Pyrimidine compounds such as 5-fluorouracil (5FU) have been used as anti-neoplastic agents.
  • the anti-cancer activity of 5FU and similar compounds is believed to be due to a "suicide substrate" mechanism where the 5FU inhibits thymidylate synthase, an enzyme important in DNA synthesis.
  • pyrimidine and dihydropyrimidine compounds administered according to the invention for the treatment of convulsive disorders do not significantly inhibit thymidylate synthase.
  • inhibition of thymidylate synthase by pyrimidine compounds is increased by the presence of electronegative groups at the 5-position of the pyrimidine ring (i.e., R 9 of Formula 5), and can therefore be decreased by providing such compounds with non-electronegative groups at the 5-position of the pyrimidine ring (i.e., R 9 of Formula 5). It is further believed that by providing substituents with sufficient steric bulk to decrease the ability of the pyrimidine compound to bind to thymidylate synthase, inhibition of thymidylate synthase can be decreased.
  • R 9 is a non-electronegative (i.e., neutral or electropositive) group (e.g., alkyl, aryl, or the like).
  • at least one of R 9 and R 10 of Formula V is a sterically bulky group (e.g., long-chain or branched alkyl, substituted aryl, or the like), or R 9 and R 10 are joined to form a carbocyclic or heterocyclic ring.
  • pyrimidine and dihydropyrimidine compounds for use according to the invention, together with illustrative active metabolites thereof, are shown in Figure 1.
  • uracil and dihydrouracil compounds which are analogous to ⁇ -alanines are within the scope of the present invention including, for example, the following:
  • substituted or unsubstituted uracils, and derivatives or analogs thereof may be especially advantageous as certain uracil compounds have been found to have anti-ictogenic properties (only) when tested in an anti-seizure model in rats.
  • uracil compounds have been found to have anti-ictogenic properties (only) when tested in an anti-seizure model in rats.
  • the prodrug form of the compound (a uracil) can have anti-seizure activity, while the metabolically-produced ⁇ -amino anionic compounds can have anti-epileptogenic and/or anti-convulsive activity.
  • an active agent of the invention antagonizes NMDA receptors by binding to the glycine binding site of the NMDA receptors.
  • the agent augments GABA inhibition by decreasing glial GABA uptake.
  • the agent is administered orally.
  • the method further includes administering the agent in a pharmaceutically acceptable vehicle.
  • 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.
  • Blockers of sodium and/or calcium ion channel activity are well known in the art and, can be used as the A moiety (as described hereinbelow in the context of bifunctional molecules) in the compounds and methods of the present invention.
  • any compound which opens potassium or chloride ion channels can be used as the A moiety in the compounds and methods of the present invention.
  • Antagonists of NMDA receptors and augmenters of endogenous GABA inhibition are also known to one of skill in the art and can be used in the methods and compounds of the invention.
  • 2,3-quinoxalinediones are reported to have NMDA receptor antagonistic activity (See, e.g., U.S. Patent No.
  • Exemplary calcium and zinc chelators include moieties known in the art for chelation of divalent cations, including ethylenediaminetetraacetic acid (EDTA), ethylene glycol bis(beta-aminoethyl ether)-N,N,N',N'- tetraacetic acid, and the like, in addition to those mentioned supra.
  • EDTA ethylenediaminetetraacetic acid
  • ethylene glycol bis(beta-aminoethyl ether)-N,N,N',N'- tetraacetic acid and the like, in addition to those mentioned supra.
  • Exemplary iron chelators include enterobactin, pyridoxal isonicotinyl hydrazones, N,N'-bis(2-hydroxybenzoyl)- ethylenediamine-N,N'-diacetic acid (HBED), and l-substituted-2-alkyl-3-hydroxy-4-pyridones, including l-(2'-carboxyethyl)-2-methyl-3-hydroxy-4-pyridone, and other moieties known in the art to chelate iron.
  • enterobactin enterobactin
  • pyridoxal isonicotinyl hydrazones N,N'-bis(2-hydroxybenzoyl)- ethylenediamine-N,N'-diacetic acid (HBED)
  • l-substituted-2-alkyl-3-hydroxy-4-pyridones including l-(2'-carboxyethyl)-2-methyl-3-hydroxy-4-pyridone
  • N ⁇ -substituted arginine analogs especially of the L-configuration, including L- N ⁇ -nitro-arginine (a specific inhibitor of cerebral NO synthase), L-N ⁇ -amino-arginine, and L- N ⁇ -alkyl-arginines; or an ester thereof, preferably the methyl ester.
  • exemplary antioxidants include ascorbic acid, tocopherols including alpha-tocopherol, and the like.
  • the invention provides a method for inhibiting a convulsive disorder.
  • the method includes the step of administering to a subject in need thereof an effective amount of a dioxapiperazine (also known as diketopiperazine) compound represented by the formula (Formula IV):
  • R 7 is hydrogen, alkyl, mercaptoalkyl, alkenyl, alkynyl, cycloalkyl, aryl, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aryloxycarbonyl, cyano, carboxyl, alkoxycarbonyl, aryloxycarbonyl, or -(CH 2 ) n -Y, where n is an integer from 1 to 4 and Y is a heterocyclic moiety selected from the group consisting of thiazolyl, triazolyl, and imidazolyl; and R 6 and R 6* are each independently hydrogen, alkyl, alkylcarbonyl or arylcarbonyl; or a pharmaceutically acceptable salt thereof; such that the convulsive disorder is inhibited.
  • R 7 is not hydrogen, methyl or phenyl.
  • the compound is cyclo-D-phenylglycyl-(S-Me)-L-cysteine.
  • the invention provides a method for concurrently inhibiting epileptogenesis and ictogenesis, the method including the step of administering to a subject in need thereof an effective amount of a compound of the formula: where Ar represents an unsubstituted or substituted aryl group; R 7 is hydrogen, alkyl, mercaptoalkyl, alkenyl, alkynyl, cycloalkyl, aryl, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aryloxycarbonyl, cyano, carboxyl, alkoxycarbonyl, aryloxycarbonyl, or -(CH 2 ) n -Y, where n is an integer from 1 to 4 and Y is a heterocyclic moiety selected from the group consisting of thiazolyl, triazolyl, and imidazolyl; R 6 is hydrogen or alkyl, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl or aryloxy
  • the invention provides a method for treating a disorder associated with NMDA receptor antagonism.
  • the method includes the step of administering to a subject in need thereof an effective amount of a compound of the formula:
  • R 7 is hydrogen, alkyl, mercaptoalkyl, alkenyl, alkynyl, cycloalkyl, aryl, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aryloxycarbonyl, cyano, carboxyl, alkoxycarbonyl, aryloxycarbonyl, or -(CH 2 ) n -Y, where n is an integer from 1 to 4 and Y is a heterocyclic moiety selected from the group consisting of thiazolyl, triazolyl, and imidazolyl; R 6 is hydrogen or alkyl, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl or aryloxycarbonyl; and R 6* is an NMDA antagonist moiety; or a pharmaceutically acceptable salt thereof; such that the disorder associated with NMDA receptor antagonism is treated.
  • R 7 is not hydrogen, methyl or phenyl.
  • the invention provides a method for inhibiting ictogenesis and epileptogenesis in a subject.
  • the method includes the step of administering to a subject in need thereof an effective amount of an agent represented by the formula A-B, where A is a domain having sodium ion channel blocking activity; and B is a domain having at least one activity selected from the group consisting of NMDA receptor antagonism; GABA inhibition augmentation; calcium binding; iron binding; zinc binding; NO synthase inhibition; and antioxidant activity; such that epileptogenesis is inhibited in the subject.
  • the domains A and B e.g., pharmacophores
  • A is a dioxapiperazine moiety, a phenytoin moiety, or a carbamazepine moiety.
  • the invention provides a method for inhibiting ictogenesis and epileptogenesis in a subject.
  • the method includes the step of administering to a subject in need thereof an effective amount of an agent represented by the formula A-B, where A is a domain having anti-ictogenic activity; and B is a domain having at least one activity selected from the group consisting of NMDA receptor antagonism; GABA inhibition augmentation; calcium binding; iron binding; zinc binding; NO synthase inhibition; and antioxidant activity; such that epileptogenesis is inhibited in the subject.
  • the domains A and B (e.g., pharmacophores) of the agent are covalently linked.
  • A is a dioxapiperazine moiety, a phenytoin moiety, or a carbamazepine moiety.
  • a hybrid drug according to the invention can be a bifunctional molecule created by connecting an anti-ictogenic moiety with an anti-epileptogenic moiety via, preferably, a covalent linkage such as an amide bond or an ester bond.
  • the linkage can optionally be cleavable in vivo.
  • the linkage can also include a linker or spacer moiety to provide flexibility or sufficient space between the A and B moieties to permit interaction with the respective moieties to which A and B bind or with which A and B interact.
  • linkers include diacids such as adipic acid, e.g., to link amino group-containing A and B moieties; or diamines such as 1,6-hexanediamine, e.g., to link carboxyl group-containing A and B moieties; or amino acids, e.g., to link an amino-functionalized B moiety to a carboxy-functionalized A moiety or vice versa.
  • a linker can be selected to provide desired properties according to considerations well known to one of skill in the art.
  • the bifunctional molecule thus targets both ictogenesis and epileptogenesis.
  • a hybrid drug may comprise one or more desired average pharmacophores.
  • a method for inhibiting epileptogenesis and/or ictogenesis in a subject involves administering to a subject an effective amount of a compound such that epileptogenesis is inhibited, where the compound is of Formula X
  • R 1 is hydrogen, alkyl, alkenyl, alkynyl, aryl, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, or aryloxycarbonyl
  • R 2 is alkyl, alkenyl, alkynyl, aryl, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, or aryloxycarbonyl
  • G is an anionic group at physiological pH; and pharmaceutically acceptable salts or esters thereof.
  • G is carboxyl.
  • R 1 is hydrogen.
  • R 2 is alkyl, e.g., arylalkyl such as phenylalkyl.
  • Examples of compounds of Formula X include
  • a method for inhibiting epileptogenesis and/or ictogenesis in a subject involves administering to a subject an effective amount of a compound such that epileptogenesis is inhibited, where the compound is either of the following:
  • a method for inhibiting epileptogenesis and/or ictogenesis in a subject involves administering to a subject an effective amount of a compound such that epileptogenesis is inhibited, where the compound is of Formula XI
  • G is an anionic group at physiological pH
  • D is a phenoxy substituted phenyl group
  • pharmaceutically acceptable salts or esters thereof
  • G is a carboxyl group.
  • D is an alkylphenoxy substituted phenyl group, e.g., a methylphenoxy substituted phenyl group, or a halophenoxy substituted phenyl group, e.g., a chlorophenoxy substituted phenyl group.
  • Examples of compounds of Formula XI include
  • a method for inhibiting epileptogenesis and/or ictogenesis in a subject involves administering to a subject an effective amount of a compound such that epileptogenesis is inhibited, where the compound is of Formula XII
  • G is an anionic group at physiological pH
  • E is an aryl group substituted with, 2 or more alkoxy or aryloxy moieties; and pharmaceutically acceptable salts or esters thereof.
  • G is a carboxyl group.
  • E is a phenyl group substituted with 2 or more alkoxy or aryloxy moieties.
  • E is a phenyl group substituted with 2 or more alkoxy (i.e. methoxy) groups.
  • Examples of compounds of Formula XII include
  • a method for inhibiting epileptogenesis and/or ictogenesis in a subject comprises administering to a subject an effective amount of a compound such that epileptogenesis is inhibited, where the compound is of Formula XIII
  • G is an anionic group at physiological pH; n is 1 to 3; F is a phenyl substituted methyl; and pharmaceutically acceptable salts or esters thereof.
  • G is a carboxyl group.
  • n is 1 and F is a diphenyl substituted methyl.
  • Examples of compounds of Formula XIII include
  • Compounds which find use in the therapeutic methods of the invention can be determined through routine screening assays.
  • the animal model of Phase 1 epileptogenesis described in the Examples, infra can be employed to determine whether a particular compound has anti-epileptogenic activity against Phase 1 epileptogenesis.
  • 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).
  • 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.
  • 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.
  • the invention provides compounds useful for the treatment of epilepsy and convulsive disorders, including epileptogenesis and ictogenesis.
  • the invention provides a dioxapiperazine compound of the formula (Formula IV)
  • R 7 is hydrogen, alkyl, mercaptoalkyl, alkenyl, alkynyl, cycloalkyl, aryl, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aryloxycarbonyl, cyano, carboxyl, alkoxycarbonyl, aryloxycarbonyl, or -(CH 2 ) n -Y, where n is an integer from 1 to 4 and Y is hydrogen or a heterocyclic moiety selected from the group ⁇ nsisting of thiazolyl, triazolyl, and imidazolyl-, and R 6 and R 6* are each independently hydrogen, alkyl, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl or aryloxycarbonyl; or a pharmaceutically acceptable salt thereof.
  • the carbon atom to which the Ar group is attached has the D configuration.
  • Ar is an unsubstituted or substituted phenyl group.
  • Y is hydrogen.
  • at least one of R 6 and R 6* is selected from the group consisting of an antioxidant moiety, an NMDA antagonist, an NO synthase inhibitor, an iron chelator moiety, a Ca(II) chelator moiety, and a Zn(II) chelator moiety.
  • R 7 is methyl or mercaptomethyl.
  • R 6 and R ⁇ * are both hydrogen.
  • the compound is cyclophenylglycyl-2-(amino-3- mercaptobutanoic acid), more preferably cyclo-D-phenylglycyl-L- ⁇ 2-(amino-3- mercaptobutanoic acid) ⁇ .
  • the compound is cyclo-D-phenylglycyl- (S-Me)-L-cysteine.
  • Ar is an unsubstituted phenyl group.
  • R 7 is not hydrogen, methyl or phenyl.
  • the invention provides a compound of the formula (Formula IV)
  • R 7 is, alkyl, mercaptoalkyl, alkenyl, alkynyl, cycloalkyl, aryl, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aryloxycarbonyl, cyano, carboxyl, alkoxycarbonyl, aryloxycarbonyl, or -(CH 2 ) favor-Y, where n is an integer from 1 to 4 and Y is hydrogen or a heterocyclic moiety selected from the group consisting of thiazolyl, triazolyl, and imidazolyl; R 6 is hydrogen or alkyl, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl or aryloxycarbonyl; and R 6* is selected from the group consisting of an antioxidant moiety, an NMDA antagonist, an NO synthase inhibitor, an iron chelator moiety, a Ca(II) chelator
  • R 6* is D- - aminoadipyl.
  • R 7 is mercaptomethyl.
  • R 7 is not hydrogen, methyl or phenyl.
  • R 6* further comprises a cleavable linkage.
  • the compound comprises cyclo-D- phenylglycyl-L-alanine .
  • the compounds of the invention include compounds which can have a single pharmacophore (e.g., dioxapiperazines where the dioxapiperazine moiety is the sole pharmacophore); or ⁇ -amino anionic moieties where the ⁇ -amino anionic moiety is responsible for the biochemical activity of the compound.
  • Certain compounds of the invention include two distinct pharmacophores and have a structure represented by A-B, where A and B are each domains or pharmacophores having biochemical activity (e.g., an anticonvulsant dioxapiperazine moiety having a distinct antioxidant moiety, e.g., R 6* ) (also referred to herein as a "hybrid" drug).
  • a compound which includes two pharmacophores can be capable of interaction with two or more distinct receptors.
  • the pharmacophores can be linked to each other by a variety of techniques known to the skilled practitioner.
  • the pharmacophore represented by R 6* can be covalently bonded to a dioxapiperazine moiety through an amide linkage to a nitrogen of the dioxapiperazine ring.
  • a linkage between two pharmacophores can be selected such that the two pharmacophores are cleaved from each other in vivo (e.g., by the selection of a linkage which is labile in vivo).
  • hybrid biologically labile linkages
  • a "hybrid" two- pharmacophore drug can be designed to be transported within the body to reach a site or organ such as the brain, where one or more pharmacophore moieties exert a biological effect, at which site the hybrid drug can be cleaved to provide two active drug moieties.
  • the invention further contemplates the use of prodrugs which are converted in vivo to the therapeutic compounds of the invention.
  • prodrugs can be used to alter the biodistribution (e.g., to allow compounds which would not typically cross the blood-brain barrier to cross the blood-brain barrier) or the pharmacokinetics of the therapeutic compound.
  • an anionic group e.g., a carboxylate or sulfonate
  • the ester When the carboxylate or sulfonate ester is administered to a subject, the ester is cleaved, enzymatically or non-enzymatically, to reveal the anionic group.
  • an ester can be cyclic, e.g., a lactone or sultone, or two or more anionic moieties may be esterified through a linking group.
  • An anionic group can be esterified with moieties (e.g., acyloxymethyl esters) which are cleaved to reveal an intermediate compound which subsequently decomposes to yield the active compound.
  • an anionic moiety can be esterified to a group which is actively transported in vivo, or which is selectively taken up by target organs.
  • the ester can be selected to allow specific targeting of the therapeutic moieties to particular organs.
  • the prodrug is a reduced form of an anionic group, e.g., a carboxylate or sulfonate, e.g., an alcohol or thiol, which is oxidized in vivo to the therapeutic compound.
  • preferred compounds include pyrimidines, such as substituted uracils, which can be converted in vivo to ⁇ -amino anionic compounds.
  • the compound can be represented by the formula (Formula V):
  • R 9 and R 10 are each independently selected from the group consisting of hydrogen, alkyl (including cycloalkyl, heterocyclyl, and aralkyl), alkenyl, alkynyl, aryl, alkoxy, aryloxy, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aryloxycarbonyl, amino (including unsubstituted and substituted amino), hydroxy, thiol, alkylthiol, nitro, cyano, halogen, carboxyl, alkoxycarbonyloxy, aryloxycarbonyloxy or aminocarbonyl; or R 9 and R 10 , together with the two-carbon unit to which they are attached, are joined to form a carbocyclic or heterocyclic ring having from 4 to 8 members in the ring; and R 11 is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, alkylcarbonyl, arylcarbonyl,
  • the compound can be represented by the formula (Formula Va): where R 9a , R 9b , R IOa , R 10b are each independently selected from the group consisting of hydrogen, alkyl (including cycloalkyl, heterocyclyl, and aralkyl), alkenyl, alkynyl, aryl, alkoxy, aryloxy, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aryloxycarbonyl, amino (including unsubstituted and substituted amino), hydroxy, thiol, alkylthiol, nitro, cyano, halogen, carboxyl, alkoxycarbonyloxy, aryloxycarbonyloxy or aminocarbonyl; or R 9a and R 9b , together with the two-carbon unit to which they are attached, are joined to form a carbocyclic or heterocyclic ring having from 4 to 8 members in the ring; or R 10a and R 10b , together with the two
  • a preferred group of compounds according to the invention include
  • R 9 (each selected independently of other R 9 groups, if any), R 11 , and R 12 are defined above.
  • Another preferred group of compounds include
  • R 9 , R 10 , R n , and R 12 are defined above. More preferred are the following compounds
  • R 9 (each selected independently of other R 9 groups, if any), R 11 , and R 12 are defined above.
  • R 9 each selected independently of other R 9 groups, if any
  • R 10 , R n , and R 12 are defined above, and including all possible stereoisomers.
  • Compounds of Formulas V - Vf can be prepared according to a variety of synthetic procedures, some of which are known in the art. Exemplary syntheses are shown in Figure 2.
  • a barbituric acid compound can be modified (e.g., by mesylation with mesyl chloride and an amine base) to provide a compound which can be further functionized (e.g., by Michael addition of a suitable nucleophile); or can be reductively desulphonated to provide a dienophile for subsequent Diels- Alder cycloaddition with a suitable dienophile. Reduction of the uracil ring provides dihydrouracil derivatives.
  • 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.
  • the compound may include a moiety capable of targeting the compound to the brain, by either active or passive transport (a "targeting moiety").
  • 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. Thus, drug accumulates in the brain.
  • 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 container of 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.
  • a convulsive disorder e.g., epileptogenesis
  • the kits of the invention provide convenient means for administering the compounds of the invention.
  • the kit includes a therapeutically effective amount of the compound, more preferably in unit dosage form.
  • the invention provides libraries of compounds of Formula IV, Formula V - Vf, or Formula XIV, and methods of preparing such libraries.
  • the invention includes methods for synthesis of combinatorial libraries of compounds of Formula IV, Formula V - Vf, or Formula XIV.
  • Such libraries can be synthesized according to a variety of methods. For example, a "split-pool" strategy can be implemented to produce a library of compounds. The library of immobilized compounds can then be washed to remove impurities. In certain embodiments, the immobilized compounds can be cleaved from the solid support to yield a compound of Formula IV, Formula V - Vf, or Formula XIV.
  • a "diversomer library” is created by the method of Hobbs, DeWitt et al. (Proc. Natl. Acad. Sci. U.S.A. 90:6909 (1993)). After creation of the library of compounds, purification and workup yields a soluble library of substituted compounds of Formula IV, Formula V - Vf, or Formula XIV.
  • Other synthesis methods including the "tea-bag” technique of Houghten et al., Nature 354:84-86 (1991), can also be used to synthesize libraries of compounds according to the subject invention.
  • Combinatorial libraries can be screened to determine whether any members of the library have a desired activity, and, if so, to identify the active species. Methods of screening combinatorial libraries have been described (see, e.g., Gordon et al, JMed. Chem., op. cit.). Soluble compound libraries can be screened by affinity chromatography with an appropriate receptor to isolate ligands for the receptor, followed by identification of the isolated ligands by conventional techniques (e.g., mass spectrometry, NMR, and the like).
  • Immobilized compounds can be screened by contacting the compounds with a soluble receptor; preferably, the soluble receptor is conjugated to a label (e.g., fluorophores, colorimetric enzymes, radioisotopes, luminescent compounds, and the like) that can be detected to indicate ligand binding.
  • a label e.g., fluorophores, colorimetric enzymes, radioisotopes, luminescent compounds, and the like
  • immobilized compounds can be selectively released and allowed to diffuse through a membrane to interact with a receptor.
  • Exemplary assays useful for screening the libraries of the invention are known in the art (see, e.g., E.M. Gordon et al, J. Med. Chem. 37:1385-1401 (1994)).
  • Combinatorial libraries of compounds can also be synthesized with "tags" to encode the identity of each member of the library. See, e.g., U.S. Patent No. 5,565,324 and PCT Publication No. WO 94/08051).
  • this method features the use of inert, but readily detectable, tags, that are attached to the solid support or to the compounds.
  • tags When an active compound is detected such as by one of the techniques described above, the identity of the compound is determined by identification of the unique accompanying tag.
  • This tagging method permits the synthesis of large libraries of compounds which can be identified at very low levels.
  • the libraries of compounds of the invention contain at least
  • the libraries of compounds of the invention contain fewer than 10 9 compounds, more preferably fewer than 10 8 compounds, and still more preferably fewer than 10 7 compounds.
  • a library of compounds is preferably substantially pure, i.e., substantially free of compounds other than the intended products, e.g., members of the library.
  • the purity of a library produced according to the methods of the invention is at least about 50%, more preferably at least about 70%, still more preferably at least about 90%, and most preferably at least about 95%.
  • the libraries of the invention can be prepared as described herein.
  • at least one starting material used for synthesis of the libraries of the invention is provided as a variegated population.
  • the term "variegated population”, as used herein, refers to a population including at least two different chemical entities, e.g., of different chemical structure.
  • a "variegated population" of compounds of Formula XIV would comprise at least two different compounds of Formula XIV.
  • Use of a variegated population of linkers to immobilize compounds to the solid support can produce a variety of compounds upon cleavage of the linkers.
  • Libraries of the invention are useful for, inter alia, drug discovery.
  • a library of the invention can be screened to determine whether the library includes compounds having a pre-selected activity, e.g., anti-epileptogenic or anticonvulsant activity.
  • This invention provides anti-ictogenic and/or anti-epileptogenic compounds of the formula (Formula XIV)
  • R 9 is hydrogen, alkyl, alkynyl, aryl, amino, hydroxy, halogen, nitro, carboxyl, or R 9 and R 10 together form a 5- or 6- membered carbocyclic or heterocyclic ring
  • R 10 is hydrogen, alkyl, aryl, carboxyl, or R 9 and R 10 together form a 5- or 6-membered carbocyclic or heterocyclic ring
  • R ⁇ is hydrogen, alkyl, aryl (including hydroxyalkyl), thioether, amino, or tetrahydrofuranyl (including substituted tetrahydrofurans, such as ribose and other carbohydrates)
  • R 12 is hydrogen, alkyl (including hydroxyalkyl), aryl, amino, or thioether; or pharmaceutically acceptable salts or esters thereof.
  • R° is alkyl such as methyl, ethyl, propyl, and butyl or hydroxyalkyl (i.e. hydroxymethyl, hydroxyethyl, hydroxypropyl, and hydroxybutyl). Desirably R° is bromine, fluorine, chlorine, or iodine. More desirably, R 9 is alkynyl (i.e. ethynyl, propynyl, butynyl, pentynyl, and hexynyl). Desirably, R 9 is thioether.
  • R 10 is hydrogen. Desirably R 10 is alkyl (e.g. methyl, ethyl, propyl, or butyl.)
  • R 11 is hydrogen, or alternately alkyl such as isopropyl, sec-butyl, arylalkyl, or phenylalkyl (e.g., nitro-substituted phenylalkyl.)
  • R 12 is hydrogen, or alternately alkyl, such as arylalkyl or phenylalkyl (e.g., nitro- substituted phenylalkyl).
  • R 9 is bromine
  • R ]0 is hydrogen
  • R 12 is hydrogen
  • R !0 is hydrogen
  • R !0 is hydrogen
  • R" is arylalkyl
  • R r2 is hydrogen.
  • Some preferred R ⁇ and R' 2 groups include hydrogen, methyl, ethyl, isopropyl, sec- butyl, benzyl (including para- ⁇ tr ⁇ benzyl), and cyclohexylmethyl.
  • R 9 is hydrogen, R'° is hydrogen, R ⁇ is arylalkyl, and R 12 is hydrogen.
  • R 9 is bromine
  • R 10 is hydrogen
  • R u is arylalkyl
  • R 12 is hydrogen. Examples of the above compounds include compounds P I - P43 (see Table, below) and pharmaceutically acceptable salts and esters thereof.
  • an anti-convulsive pharmaceutical composition can include an amount of one or more of the above compounds effective to inhibit a convulsive disorder such as epilepsy in a subject in need thereof, and a pharmaceutically acceptable carrier.
  • Ictogenesis may be treated or prevented in a subject in need thereof by administering to the subject an amount of one or more of the above compounds to inhibit ictogenesis in the subject so that ictogenesis is treated or prevented in the subject.
  • epileptogenesis may be treated or prevented in a subject in need thereof by administering to the subject an amount of one or more of the above compounds to inhibit epileptogenesis in the subject so that epileptogenesis is treated or prevented in the subject.
  • kits for treating or preventing ictogenesis (or epileptogenesis) in a subject may include one of the above compounds, and instructions for administering a therapeutically effective amount of a compound to the subject so that ictogenesis (or epileptogenesis) is treatec 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 to the NMDA receptors of the neurons of the subject's brain so that an epileptogenic condition is diagnosed in the subject.
  • Compound labeled with a detectable marker includes compounds that are labeled by a detectable means and includes enzymatically, radioactively, fluorescentiy, chemiluminescently, and/or bioluminescently labeled antibodies.
  • enzymes that can be used as labeled include malate dehydrogenase, staphylococcal nuclease, delta-V-steroid isomerase, yeast alcohol dehydrogenase, alpha- glycerophosphate dehydrogenase, triose phosphate isomerase, horseradish peroxidase, alkaline phosphatase, asparaginase, glucose oxidase, beta-galactosidase, ribonuclease, urease, catalase, glucose-VI-phosphate dehydrogenase, gmcoamylase and acetylcholinesterase.
  • radioactive labels include 3 H, 125 1, 131 1, 35 S, and 14 C, where 125 I is preferred.
  • fluorescent labels include fluorescein isothiocyanate, rhodamine, phycoerytherin, phycocyanin, allophycocyanin, ⁇ -phthaldehyde and fiuorescamine.
  • chemiluminescent labels include luminol, luciferin, isoluminol, theromatic acridinium ester, imidazole, acridinium salt and oxalate ester.
  • bioluminescent labels include luciferin. luciferase and aequorin.
  • This invention further relates to a method of treating or preventing seizures, e.g., epileptic seizures, in a subject suffering from head trauma including administering to the gubjeet an amount of on ⁇ of the above compounds so that seizures are treated or prevented in the subject.
  • seizures e.g., epileptic seizures
  • compounds according to Formulas Vb - Vf and XIV are preferred in the present invention
  • compounds according to Formulas V - Vf, IV, X, XI, XII, and XIII, as well as those disclosed in PCT publication WO 98/40055 (attorney docket no. NCI-006PC) and corresponding U.S. and other national and regional phase applications and patents may also be used in the methods of the present invention.
  • 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) and/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 or spray applied to the skin; or (4) intravaginally or intrarectally, for example, as a pessary, cream or foam.
  • the therapeutic compound is administered orally.
  • the compounds of the invention can be formulated as pharmaceutical compositions for administration to
  • the compounds of the invention are administered to subjects in a biologically compatible form suitable for pharmaceutical administration in vivo.
  • 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.
  • subject is intended to include living organisms where an immune response can be elicited, e.g., mammals. Examples of subjects include humans, dogs, cats, mice, rats, and transgenic species thereof.
  • 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.
  • 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
  • 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.
  • pharmaceutically acceptable carrier as used herein is intended to include diluents such as saline and aqueous buffer solutions.
  • 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.
  • compositions suitable for injectable use include sterile aqueous solutions (where water soluble) or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersion.
  • the composition must be sterile and must be fluid to the extent that easy syringability exists. It must be stable under the conditions of manufacture and storage and must 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.
  • isotonic agents for example, sugars, polyalcohols such as manitol, 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.
  • dispersions are prepared by incorporating the active compound into a sterile vehicle which contains a basic dispersion medium and the required other ingredients from those enumerated above.
  • 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.
  • the composition may be orally administered, for example, with an inert diluent or an assimilable edible carrier.
  • 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.
  • Dosage unit form 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.
  • Preferred compounds of the invention also include lH-pyrimidine-2,4-dione, 5-methyl- 1 H-pyrimidine-2,4-dione, 5 -hy droxymethyl- 1 H-pyrimidine-2,4-dione, 5 -hydroxy- 1 H- pyrimidine-2,4-dione, 5-bromo-lH-pyrimidine-2,4-dione, 5-iodo-lH-pyrimidine-2,4-dione, 6- methyl-lH-pyrimidine-2,4-dione, 5-bromo-6-methyl-l ⁇ -pyrimidine-2,4-dione, 6-methyl-5- nitro- lH-pyrimidine-2,4-dione, 5-amino-2,6-dioxo-l,2,3,6-tetrahydro-pyrimidine-4-carboxylic acid, 2,6-dioxo-l,2,3,6-tetrahydro-pyrimidine-4-carboxylic acid
  • Still more preferred compounds include 5-methylsulfanylmethyl-lH-pyrimidine-2,4- dione, 1 -benzyl-5-iodo- 1 H-pyrimidine-2,4-dione, 6-methyl- 1 ,3 -bis-(4-nitro-benzyl)- 1 H- pyrimidine-2,4-dione, 1 -methyl- 1 H-pyrimidine-2,4-dione, 1 ,3-dimethyl- 1 H-pyrimidine-2,4- dione, 1 ,3 -diisopropyl- 1 H-pyrimidine-2,4-dione, 1 ,3 -bis-(3 -hydroxy-propyl)- 1 H-pyrimidine- 2,4-dione, 3-amino-l-benzyl-dihydro-pyrimidine-2,4-dione, 3-amino-l-benzyl-6-methyl- dihydro-pyrimidine-2,4-dione, 6-phenyl-d
  • the resin was removed by filtration, and the filtrate was concentrated by vacuum distillation to a volume of approximately 25 mL.
  • the solution was allowed to cool to room temperature, then further cooled in an ice bath to precipitate the product as a white solid. Recrystallization of the product was performed from water-methanol (volume ratio 1 :2) and the product was filtered out, washed with cold methanol and dried under high vacuum to yield 827 mg of a fine white powder (54.4% yield) showing a single on TLC, with the R f value 0.69 (methanol solvent) and properties given below.
  • the triethylamine was distilled off under reduced pressure to obtain a brownish yellow slurry to which 50.0 mL of EtOAc was added and then extracted twice with 50.0 mL of a 5% aqueous solution of the sodium salt of ethylenediaminetetraacetic acid (EDTA) and once with 50.0 mL of distilled water.
  • EDTA ethylenediaminetetraacetic acid
  • the supernatant foaming substance was isolated by decanting off the aqueous phase and washed with water, filtered and air dried to obtain white solid that showed two different spots on TLC.
  • the organic phase was completely distilled off to produce a brown-red oil from which reaction products were obtained by crystallization from ethyl acetate (EtOAc)/hexanes. These products were found to be identical to those from the foaming substance, as by TLC, and were all mixed prior to separation and purification.
  • R Alkyl groups Bl B2
  • 5-hexynyluracil and 6-n-butylfuranopyrimidin-2-one was prepared from 3.0 g of 5-iodouracil and 3.0 mL of 1-hexyne at 50°C for 24 hours.
  • Triethylamine solvent was completely distilled off at reduced pressure and a pale yellow slurry was obtained.
  • This slurry was dissolved in 50.0 mL of DMF containing 0.70 g of KOH, and the resulting dark red solution was heated in an oil bath at 65°C for 10 minutes.
  • PIS pilocarpine induced-seizures
  • SRS spontaneous recurrent seizure
  • MES maximal electroshock induced-seizures
  • PTZ subcutaneous pentylenetetrazole induced-seizures
  • hippocampal kindling seizure model Most of test compounds PI — P 43 showed some activity in at least one of these assays.
  • PIS Pilocarpine induced-seizure
  • SRS spontaneous recurrent seizures
  • the MES model is described in, e.g., "Molecular and Cellular Targets for Anti-Epileptic Drugs” G. Avanzini, et al. (1997) John Libbey & Company Ltd., pp 191-198; Chapter 16, "The NIH Anticonvulsant Drug Development (ADD) Program: preclinical anticonvulsant screening project," by James P. Stables and Harvey J. Kupferberg.
  • the convulsant dose of pentylenetetrazole (85 mg/kg in mice and 70 mg/kg in rats) is injected at the time of peak effect of the test compound. Then, the animals are isolated and observed for a period of 30 minutes to see if seizures occur. Absence of clonic spasms persisting for five seconds or longer is an indication that the test compound may have the ability to increase the pentylenetetrazole induced-seizure threshold.
  • 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
  • Preliminary neurotoxicity induced by the test compound may be characterized by neurologic abnormalities and poor performances in given tasks.
  • 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.
  • the neurologic deficit is indicated by a circular or zigzag gait, ataxia, and other abnormal events that may include abnormal spread of legs, body posture, tremor, hyperactivity, lack of exploratory behavior, somnolence, stupor, and catalepsy.
  • Initial testings were carried out in 12 animals at doses of 30, 100, 300 mg/kg i.e. 4 animals per test, at interval times of 30 minutes and 4 hours after administering the test compound.
  • anti-ictogenic and/or anti-epileptogenic pyrimidine compounds in accordance with the invention include:
  • anti-ictogenic and/or anti-epileptogenic pyrimidine compounds in accordance with Formula XIV of the present invention include:
  • active compounds according to Formula XIV include the following:
  • active compounds according to the invention include
  • Table A Biological test results of uracils in the Pilocarpine model

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Pain & Pain Management (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)

Abstract

L'invention concerne des procédés et des composés servant à inhiber des troubles convulsifs, y compris l'épilepsie. Les procédés et les composés selon l'invention inhibent ou préviennent l'ictogénèse et/ou l'épileptogénèse. La présente invention porte également sur des procédés de préparation desdits composés. Dans un mode préféré de réalisation, les composés comprennent la formule :
EP02717913A 2001-04-11 2002-04-11 Composes de pyrimidine en tant qu'agents anti-ictogeniques et/ou anti-epileptiques Withdrawn EP1385831A2 (fr)

Applications Claiming Priority (9)

Application Number Priority Date Filing Date Title
US28298701P 2001-04-11 2001-04-11
US282987P 2001-04-11
US28594001P 2001-04-23 2001-04-23
US285940P 2001-04-23
US31074801P 2001-08-07 2001-08-07
US310748P 2001-08-07
US9993402A 2002-03-13 2002-03-13
US99934 2002-03-13
PCT/CA2002/000512 WO2002083651A2 (fr) 2001-04-11 2002-04-11 Composes de pyrimidine en tant qu'agents anti-ictogeniques et/ou anti-epileptiques

Publications (1)

Publication Number Publication Date
EP1385831A2 true EP1385831A2 (fr) 2004-02-04

Family

ID=27493095

Family Applications (1)

Application Number Title Priority Date Filing Date
EP02717913A Withdrawn EP1385831A2 (fr) 2001-04-11 2002-04-11 Composes de pyrimidine en tant qu'agents anti-ictogeniques et/ou anti-epileptiques

Country Status (4)

Country Link
EP (1) EP1385831A2 (fr)
JP (1) JP2004527535A (fr)
CA (1) CA2444148A1 (fr)
WO (1) WO2002083651A2 (fr)

Families Citing this family (20)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AU2003249812A1 (en) * 2002-07-18 2004-02-09 Queen's University At Kingston Dihydrouracil compounds as anti-ictogenic or anti-epileptogenic agents
CA2523739A1 (fr) * 2003-04-25 2004-11-11 University College Cardiff Consultants Limited Composes heterocycliques destines a etre utilises dans le traitement d'infections virales
BRPI0508310A (pt) * 2004-03-02 2007-07-24 Hoffmann La Roche derivados de 4-(sulfanil-pirimidin-4-ilmetil)-morfolina e compostos relacionados como ligandos do receptor gaba, para o tratamento de ansiedade, depressão e epilepsia
MY153733A (en) * 2008-01-30 2015-03-13 Shin Poong Pharmaceutical Co Novel quinazoline-2,4-dione derivative, and medical compositions for the prophylaxis and treatment of cranial nerve disease containing the same
DE102008030091B4 (de) * 2008-06-25 2011-03-03 Resprotect Gmbh Uracilderivate und deren Verwendung
CA2914178C (fr) 2013-01-07 2023-06-13 University Of Southern California Inhibiteurs de la desoxyuridine triphosphatase
JP6513095B2 (ja) * 2014-01-03 2019-05-15 ユニバーシティ オブ サザン カリフォルニア ヘテロ原子含有デオキシウリジントリホスファターゼ阻害剤
CN103788095A (zh) * 2014-01-20 2014-05-14 四川大学华西医院 2,4(1h,3h)-嘧啶二酮衍生物及其制备方法
CN104788389A (zh) * 2015-04-09 2015-07-22 新乡市创新生物科技有限公司 一种5-溴尿嘧啶的制备方法
WO2017006283A1 (fr) 2015-07-08 2017-01-12 Cv6 Therapeutics (Ni) Limited Inhibiteurs de désoxyuridine triphosphatase contenant une liaison cyclopropano
WO2017006282A1 (fr) 2015-07-08 2017-01-12 Cv6 Therapeutics (Ni) Limited Hydantoïne contenant des inhibiteurs de la désoxyuridine triphosphatase
WO2017006270A1 (fr) 2015-07-08 2017-01-12 University Of Southern California Inhibiteurs de la désoxyuridine triphosphatase
WO2017006271A1 (fr) 2015-07-08 2017-01-12 University Of Southern California Inhibiteurs de désoxyuridine triphosphatase contenant une liaison sulfonyle aminée
WO2017123823A1 (fr) * 2016-01-12 2017-07-20 Bioelectron Technology Corporation Inhibiteurs de sulfure:quinone oxydoréductase alkyle, acyle, urée, et aza-uracile
US11174271B2 (en) 2016-11-23 2021-11-16 Cv6 Therapeutics (Ni) Limited 6-membered uracil isosteres
WO2018098208A1 (fr) 2016-11-23 2018-05-31 Cv6 Therapeutics (Ni) Limited Inhibiteurs de désoxyuridine triphosphatase liés à un cycle azote
US11168059B2 (en) 2016-11-23 2021-11-09 Cv6 Therapeutics (Ni) Limited Amino sulfonyl compounds
WO2018098207A1 (fr) 2016-11-23 2018-05-31 Cv6 Therapeutics (Ni) Limited Hydantoïne contenant des inhibiteurs de la désoxyuridine triphosphatase
WO2018098206A1 (fr) 2016-11-23 2018-05-31 Cv6 Therapeutics (Ni) Limited Hydantoïne contenant des inhibiteurs de la désoxyuridine triphosphatase
US11247984B2 (en) 2017-01-05 2022-02-15 Cv6 Therapeutics (Ni) Limited Uracil containing compounds

Family Cites Families (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR900701763A (ko) * 1988-07-18 1990-12-04 하마구찌 미찌오 1-아미노-5-할로게노우라실, 그의 제조방법 및 이 화합물을 유효성분으로 함유하는 중추신경억제제
DE4300912A1 (de) * 1993-01-15 1994-07-21 Merck Patent Gmbh Chinazolinderivate
GB9400680D0 (en) * 1994-01-14 1994-03-09 Sandoz Ltd Improvements in or relating to organic compounds
US6472378B2 (en) * 1998-08-31 2002-10-29 Pro-Neuron, Inc. Compositions and methods for treatment of mitochondrial diseases
CA2362925C (fr) * 1999-02-23 2011-04-12 Regents Of The University Of California Procedes de traitement de troubles mitochondriaux
AU2001230913B2 (en) * 2000-01-14 2005-06-30 The Government Of The United States Of America, Represented By The Secretary, Department Of Health And Human Services Methanocarba cycloalkyl nucleoside analogues

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO02083651A2 *

Also Published As

Publication number Publication date
WO2002083651A2 (fr) 2002-10-24
JP2004527535A (ja) 2004-09-09
WO2002083651A3 (fr) 2002-12-19
CA2444148A1 (fr) 2002-10-24

Similar Documents

Publication Publication Date Title
US7501429B2 (en) Pyrimidine compounds as anti-ictogenic and/or anti-epileptogenic agents
EP1385831A2 (fr) Composes de pyrimidine en tant qu'agents anti-ictogeniques et/ou anti-epileptiques
US7268164B2 (en) Anti-epileptogenic agents
US20060014752A1 (en) Heterocyclic anti-epileptogenic agents and methods of use thereof
TWI440461B (zh) １ｈ-喹唑啉-２，４-二酮
US5801183A (en) Aza and aza (N-oxy) analogs of glycine/NMDA receptor antagonists
US20030194375A1 (en) Anti-epileptogenic agents
JPH11509847A (ja) ヘテロ環式化合物、それらの調製及び使用
JP2005281309A (ja) 新規な融合ピラゾリル化合物
JP5965387B2 (ja) Ｔｓｈ受容体用のインバースアゴニストおよびニュートラルアンタゴニスト
FR2684672A1 (fr) Derives de pyrimidine, utiles pour le traitement d'etats tels que l'hypertension et l'insuffisance cardiaque, et procede pour leur preparation.
US5721223A (en) Imidazo 1,2-a! Pyridinyldiacid compounds for cognitive enhancement and for treatment of cognitive disorders and neurotoxic injury
US5409926A (en) AT-2 antagonist inhibition of vascular restenosis
AU2002249037A1 (en) Pyrimidine compounds as anti-ictogenic and/or anti-epileptogenic agents
EP1011676B1 (fr) Derivees des quinolin-urees destinees au traitement du syndrome de sevrage et des lesions cerebrales provoquees par le sevrage
US6962930B1 (en) Compounds, compositions and method suitable for amelioration of withdrawal syndromes and withdrawal-induced brain damage
CA2521212A1 (fr) Agents anti-epileptogenes
AU2004242564A1 (en) Anti-epileptogenic agents
US5484793A (en) Compounds derived from 6-azaindoles as ligands of the benzodiazepine receptor and medicaments containing them
Takano et al. Synthesis and AMPA receptor antagonistic activity of a novel 7-imidazolyl-6-trifluoromethyl quinoxalinecarboxylic acid with a substituted phenyl group and improved its good physicochemical properties by introduced CF3 group
WO1996040141A1 (fr) Quinoxalinediones et quinolones pontees en position 4 et 5, et leur emploi comme antagonistes de recepteurs d'acides amines excitateurs

Legal Events

Date Code Title Description
PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

17P Request for examination filed

Effective date: 20031111

AK Designated contracting states

Kind code of ref document: A2

Designated state(s): AT BE CH CY DE DK ES FI FR GB GR IE IT LI LU MC NL PT SE TR

AX Request for extension of the european patent

Extension state: AL LT LV MK RO SI

REG Reference to a national code

Ref country code: HK

Ref legal event code: DE

Ref document number: 1063181

Country of ref document: HK

17Q First examination report despatched

Effective date: 20041209

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: THE APPLICATION IS DEEMED TO BE WITHDRAWN

18D Application deemed to be withdrawn

Effective date: 20080917

REG Reference to a national code

Ref country code: HK

Ref legal event code: WD

Ref document number: 1063181

Country of ref document: HK