WO2004009559A2 - Composes de dihydro-uracile utilises comme agents anti-ictogenes ou anti-epileptogenes - Google Patents

Composes de dihydro-uracile utilises comme agents anti-ictogenes ou anti-epileptogenes Download PDF

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WO2004009559A2
WO2004009559A2 PCT/CA2003/001082 CA0301082W WO2004009559A2 WO 2004009559 A2 WO2004009559 A2 WO 2004009559A2 CA 0301082 W CA0301082 W CA 0301082W WO 2004009559 A2 WO2004009559 A2 WO 2004009559A2
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substituted
unsubstituted
compound
epileptogenesis
epileptogenic
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WO2004009559A3 (fr
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Kathryn A. Jones
Donald F. Weaver
Kathryn E. Tiedje
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Queens University at Kingston
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Queens University at Kingston
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    • 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
    • C07D239/20—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D239/22—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms directly attached to ring carbon atoms
    • 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

Definitions

  • 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.”
  • Ictogenesis the initiation and propagation of a seizure in time and space
  • 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"
  • epileptogenesis 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).
  • triggering event e.g., brain trauma
  • 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.
  • NMDA N- methyl-D-aspartate
  • GABA gamma-amino-butyric acid
  • ⁇ -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.
  • anticonvulsant is synonymous with the terms “anti-seizure” or “anti-ictogenic;”
  • 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:
  • each R group i.e., Rl, R ⁇ , R3, R ? R5 ; gjyj R6) ma y 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 un
  • 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) n O(CH2) n - (where each n is 1, 2, or 3) group.
  • R 1 is H or NH2
  • R 2 or R 5 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, ⁇ -bromophenyl, m-bromophenyl, m- nitrophenyl, o-nitrophenyl, phenyl, p-nitrophenyl, m-methylphenyl, ?-methoxyphenyl, m- methyl
  • 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.
  • 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.
  • a convulsive disorder or condition e.g., epilepsy
  • 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.
  • 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).
  • an anti-epileptogenic agent e.g., compounds of the Formulae herein, e.g., Formula I.
  • 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).
  • an anti-epileptogenic agent e.g., compounds of the Formulae herein.
  • 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,
  • the anti-epileptogenic agent has a pharmaceutically acceptable neurotoxicity.
  • 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.
  • the effective amount is effective to treat an epileptogenesis-associated state in a subject.
  • epilepsy traumatic brain injury (TBI)
  • TBI traumatic brain injury
  • neurosurgery pain, stroke, anxiety, schizophrenia, multiple sclerosis, amyotrophic lateral sclerosis, psychoses, cerebral ischemia, Huntington's chorea, motor neuron disease, Alzheimer's disease, and dementia.
  • 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.
  • 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.
  • 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 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.
  • 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.
  • epileptogenesis-associated disorders includes disorders of the central and peripheral nervous system that may advantageously be treated by the compounds of the invention.
  • 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.
  • 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.
  • 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.
  • CNS central nervous system
  • 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).
  • anti-epileptogenic agents include compounds of the Formulae herein, and pharmaceutically acceptable salts, esters, N-substituted analogs, and prodrugs thereof.
  • 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.”
  • anticonvulsant agent includes agents capable of inhibiting (e.g., preventing, slowing, halting, or reversing) ictogenesis when the agent is administered to a subject.
  • 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.
  • TBI traumatic brain injury
  • 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.
  • 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.
  • 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.
  • substituted includes substituents which may be placed on the moiety and which allow the molecule to perform its intended function.
  • 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 .3CH 2 (halogen), (CR'R") 0 -3CONR'R", (CR'R")o-3S(O) ⁇ _ 2 NR'R", (CR'R") 0 -3CHO, (CR'R") 0 .
  • 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) n O(CH2) n - (where each n is 1 , 2, or 3) group, etc.
  • 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.
  • preferred heterocyclic groups include pyridyl, furanyl, thiophenyl, morpholinyl, and indolyl groups.
  • 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.
  • straight-chain alkyl groups e.g., methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl,
  • 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.
  • 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.
  • 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.
  • 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, sulf
  • 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)).
  • aryl e.g., phenylmethyl (i.e., benzyl)
  • alkyl also includes the side chains of natural and unnatural amino acids.
  • «- alkyl means a straight chain (i.e., unbranched) unsubstituted alkyl group.
  • alkenyl includes unsaturated aliphatic groups analogous in length and possible substitution to the alkyls described above, but that contain at least one double bond.
  • 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.
  • a straight chain or branched chain alkenyl group has 6 or fewer carbon atoms in its backbone (e.g., C2- C ⁇ for straight chain, C3-C6 for branched chain).
  • 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.
  • 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.
  • 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,
  • alkynyl includes unsaturated aliphatic groups analogous in length and possible substitution to the alkyls described above, but which contain at least one triple bond.
  • 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.
  • 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).
  • C2-Cg and C2-6 include alkynyl groups containing 2, 3, 4, 5, or 6 carbon atoms.
  • 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.
  • 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,
  • 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.
  • acyl includes compounds and moieties which contain the acyl radical (CH3CO-) or a carbonyl group.
  • 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,
  • acylamino includes moieties wherein an acyl moiety is bonded to an amino group.
  • the term includes alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido groups.
  • aroyl includes compounds and moieties with an aryl or heteroaromatic moiety bound to a carbonyl group. Examples of aroyl groups include phenylcarboxy, naphthylcarboxy, etc.
  • alkoxyalkyl includes 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.
  • alkoxy includes substituted and unsubstituted alkyl, alkenyl, and alkynyl groups covalently linked to an oxygen atom.
  • alkoxy groups include methoxy, ethoxy, isopropyloxy, propoxy, butoxy, and pentoxy groups.
  • 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
  • groups such as alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl
  • 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.
  • halogen substituted alkoxy groups include, but are not limited to, fiuoromethoxy, difluoromethoxy, trifiuoromethoxy, chloromethoxy, dichloromethoxy, trichloromethoxy, etc.
  • amine or “amino” includes compounds or moieties in which a nitrogen atom is covalently bonded to at least one carbon or heteroatom.
  • alkyl amino includes groups and compounds wherein the nitrogen is bound to at least one additional alkyl group.
  • dialkyl amino includes groups wherein the nitrogen atom is bound to at least two additional alkyl groups.
  • arylamino and diarylamino include groups wherein the nitrogen is bound to at least one or two aryl groups, respectively.
  • alkylarylamino refers to an amino group which is bound to at least one alkyl group and at least one aryl group.
  • alkaminoalkyl refers to an alkyl, alkenyl, or alkynyl group bound to a nitrogen atom which is also bound to an alkyl group.
  • 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.
  • 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.
  • alkylaminocarboxy 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.
  • 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.
  • ether includes compounds or moieties which contain an oxygen bonded to two different carbon atoms or heteroatoms.
  • alkoxyalkyl which refers to an alkyl, alkenyl, or alkynyl group covalently bonded to an oxygen atom which is covalently bonded to another alkyl group.
  • esters 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.
  • ester includes alkoxycarboxy groups such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, pentoxycarbonyl, etc.
  • hydroxy or “hydroxyl” includes groups with an -OH or -O " .
  • halogen includes fluorine, bromine, chlorine, iodine, etc.
  • perhalogenated generally refers to a moiety wherein all hydrogens are replaced by halogen atoms.
  • 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
  • Preferred heteroatoms are nitrogen, oxygen, sulfur, and phosphorus.
  • 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.
  • the invention includes novel compound or pharmaceutical compositions containing compounds of the invention described herein.
  • compounds and pharmaceutical compositions containing compounds set forth herein are part of this invention.
  • novel syntheses of the compounds of the invention described herein are also included within the scope of the present invention.
  • 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.
  • a carboxylic acid group may be esterified, e.g., with a methyl group or an ethyl group to yield an ester.
  • the 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.
  • 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.
  • 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.
  • prodrugs examples include but not limited to, 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.
  • 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
  • each R group i.e., R ⁇ , R R3, R4 ? R5 ? a ⁇ j R6
  • each R group i.e., R ⁇ , R R3, R4 ? R5 ? a ⁇ j R6
  • ma y 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 unsubsti
  • R is H or NH2;
  • R 2 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
  • 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 R 2 , R3, R5, and R ⁇ are not all hydrogen or lower alkyl.
  • the anti-ictogenic or anti-epileptogenic compound of the invention is not compound 5.
  • Exemplary compounds include those in Table 1 :
  • substituted or unsubstituted dihydrouracils may be especially advantageous as certain uracil compounds have been found to have activity when tested in an anti-seizure model in rats.
  • a prodrug form of the compound (a dihydrouracil) can have anti-seizure activity, while the metabolically-produced ⁇ -amino anionic compounds may have anti-epileptogenic or anti- convulsive activity.
  • pilocarpine hydrochloride 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.
  • 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).
  • 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.
  • pharmaceutically acceptable salt 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).
  • 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.
  • pharmaceutically acceptable salt 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.
  • 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.
  • 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.
  • NMDA N- methyl-D-aspartate
  • GABA 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 ), 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 calcium
  • 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; 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.
  • 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).
  • 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.
  • 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.
  • the agent augments GABA inhibition by decreasing glial GABA uptake.
  • the agent modulates, e.g., blocks, the GAT-1, GAT-2, or GAT-3 transporters.
  • the anti-epileptogenic agent modulates, e.g., inhibits, GABA transaminase.
  • anti- epileptogenic agent is a glutamatergic excitation modulator, e.g., inhibitor.
  • the agent is administered orally.
  • the method further includes administering the agent in a pharmaceutically acceptable vehicle.
  • 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.
  • anti-epileptogenic agent includes agents which are capable of, for example, inhibiting epileptogenesis; suppressing, e.g., inhibiting, the uptake of synaptic
  • GABA 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).
  • NMDA receptor e.g., at the strychnine insensitive glycine co-agonist site
  • 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.
  • 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.
  • 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.
  • an anionic group e.g., a carboxylate group
  • an ethyl or a fatty group can be esterified with an ethyl or a fatty group to yield a carboxylic ester.
  • the ester can be cleaved, enzymatically or non-enzymatically, to reveal the anionic group.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • pharmaceutically acceptable carrier includes 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 injection include sterile aqueous solutions (where water soluble) or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersion.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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).
  • 6-Methyl-pyrimidine-2,4- dione 6-Methyl-pyrimidine-2,4- dione, (6. 36 g, 50 mmol) was added slowly to 30 mL of cold 98% H 2 SO 4 .
  • 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 MgBr 2 *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 Na 2 SO 4 . Dichloromethane was removed under reduced pressure and the resulting oil, (3.7 g, 96%) yield), used without further purification.
  • Cinnamic acid 500 mg, 3.4 mmol
  • urea 1.0 g, 0.017 mol
  • 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 Na 2 SO 4 . Solvent was removed under reduced pressure and the product purified by recrystallization.
  • 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.
  • the first synthetic step to produce the starting materials can be used to produce dihydrouracil analogs with substitutions at the 5 and 6 position.
  • - R H, Br, Cl, methyl, ethyl, propyl, substituted or unsubstituted phenyl (e.g., NO 2 , Br, Cl, CH 3 ), substituted or unsubstituted benzyl (e.g., NO 2 , Br, Cl, CH 3 ), etc. (See substitution selection shown above for Formula I)
  • R' H, Br, Cl, ethyl, ethyl, propyl, substituted or unsubstituted phenyl (e.g., NO 2 , Br, Cl, CH 3 ), substituted or unsubstituted benzyl (e.g., NO 2 , Br, Cl, CH 3 ), etc. (See substitution selection shown above for Formula I).
  • 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.
  • PIS Pilocarpine induced-seizure
  • 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.
  • SRS spontaneous recurrent seizures
  • 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.
  • the standard anticonvulsant phenytoin can be administered (20 mg/kg/day i.v. for 10 day) at either Time 1 or Time 2.
  • MES Maximal electroshock induced-seizure
  • 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.
  • 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)
  • 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.
  • 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.
  • 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.

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Abstract

Cette invention se rapporte à des procédés et à des composés servant à inhiber les troubles convulsifs tels que l'épilepsie. Ces procédés et ces composés permettent d'inhiber ou de prévenir ou de traiter l'ictogenèse, l'épileptogenèse ou les états associés à l'épileptogenèse. Des procédés pour préparer ces composés sont également décrits. Les composés particulièrement préférés sont représentés par la formule (I).
PCT/CA2003/001082 2002-07-18 2003-07-18 Composes de dihydro-uracile utilises comme agents anti-ictogenes ou anti-epileptogenes Ceased WO2004009559A2 (fr)

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AU2003249812A AU2003249812A1 (en) 2002-07-18 2003-07-18 Dihydrouracil compounds as anti-ictogenic or anti-epileptogenic agents

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US60/397,157 2002-07-18

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US8114868B2 (en) 2008-07-25 2012-02-14 Boehringer Ingelheim International Gmbh Cyclic inhibitors of 11β-hydroxysteroid dehydrogenase 1
US8138178B2 (en) 2008-05-01 2012-03-20 Vitae Pharmaceuticals, Inc. Cyclic inhibitors of 11beta-hydroxysteroid dehydrogenase 1
US8202857B2 (en) 2008-02-11 2012-06-19 Vitae Pharmaceuticals, Inc. 1,3-oxazepan-2-one and 1,3-diazepan-2-one inhibitors of 11β-hydroxysteroid dehydrogenase 1
US8242111B2 (en) 2008-05-01 2012-08-14 Vitae Pharmaceuticals, Inc. Cyclic inhibitors of 11β-hydroxysteroid dehydrogenase 1
US8329897B2 (en) 2007-07-26 2012-12-11 Vitae Pharmaceuticals, Inc. Synthesis of inhibitors of 11β-hydroxysteroid dehydrogenase type 1
US8440658B2 (en) 2007-12-11 2013-05-14 Vitae Pharmaceuticals, Inc. Cyclic urea inhibitors of 11β-hydroxysteroid dehydrogenase 1
US8569292B2 (en) 2008-05-01 2013-10-29 Vitae Pharmaceuticals, Inc. Cyclic inhibitors of 11β-hydroxysteroid dehydrogenase 1
US8592409B2 (en) 2008-01-24 2013-11-26 Vitae Pharmaceuticals, Inc. Cyclic carbazate and semicarbazide inhibitors of 11β-hydroxysteroid dehydrogenase 1
US8592410B2 (en) 2008-05-01 2013-11-26 Vitae Pharmaceuticals, Inc. Cyclic inhibitors of 11BETA-hydroxysteroid dehydrogenase 1
US8598160B2 (en) 2008-02-15 2013-12-03 Vitae Pharmaceuticals, Inc. Cycloalkyl lactame derivatives as inhibitors of 11-beta-hydroxysteroid dehydrogenase 1
US8637505B2 (en) 2009-02-04 2014-01-28 Boehringer Ingelheim International Gmbh Cyclic inhibitors of 11beta-hydroxysteroid dehydrogenase 1
US8680281B2 (en) 2008-01-07 2014-03-25 Vitae Pharmaceuticals, Inc. Lactam inhibitors of 11-β-hydroxysteroid dehydrogenase 1
US8680093B2 (en) 2009-04-30 2014-03-25 Vitae Pharmaceuticals, Inc. Cyclic inhibitors of 11beta-hydroxysteroid dehydrogenase 1
US8765744B2 (en) 2010-06-25 2014-07-01 Boehringer Ingelheim International Gmbh Azaspirohexanones
US8835426B2 (en) 2007-02-26 2014-09-16 Vitae Pharmaceuticals, Inc. Cyclic urea and carbamate inhibitors of 11β-hydroxysteroid dehydrogenase 1
US8846613B2 (en) 2010-11-02 2014-09-30 Boehringer Ingelheim International Gmbh Pharmaceutical combinations for the treatment of metabolic disorders
US8846668B2 (en) 2008-07-25 2014-09-30 Vitae Pharmaceuticals, Inc. Inhibitors of 11beta-hydroxysteroid dehydrogenase 1
US8883778B2 (en) 2009-07-01 2014-11-11 Vitae Pharmaceuticals, Inc. Cyclic inhibitors of 11 beta-hydroxysteroid dehydrogenase 1
US8927539B2 (en) 2009-06-11 2015-01-06 Vitae Pharmaceuticals, Inc. Cyclic inhibitors of 11β-hydroxysteroid dehydrogenase 1 based on the 1,3-oxazinan-2-one structure
US8933072B2 (en) 2010-06-16 2015-01-13 Vitae Pharmaceuticals, Inc. Substituted 5-,6- and 7-membered heterocycles, medicaments containing such compounds, and their use
US9079861B2 (en) 2007-11-07 2015-07-14 Vitae Pharmaceuticals, Inc. Cyclic urea inhibitors of 11β-hydroxysteroid dehydrogenase 1
WO2018128720A1 (fr) * 2017-01-05 2018-07-12 Cv6 Therapeutics (Ni) Limited Composés contenant de l'uracile
WO2018220762A1 (fr) * 2017-05-31 2018-12-06 大塚製薬株式会社 Composé de pyrimidine
US10544105B2 (en) 2015-07-08 2020-01-28 Cv6 Therapeutics (Ni) Limited Deoxyuridine triphosphatase inhibitors containing cyclopropano linkage
US10562860B2 (en) 2015-07-08 2020-02-18 Cv6 Therapeutics (Ni) Limited Hydantoin containing deoxyuridine triphosphatase inhibitors
US10577321B2 (en) 2015-07-08 2020-03-03 University Of Southern California Deoxyuridine triphosphatase inhibitors
JP2020094045A (ja) * 2018-11-30 2020-06-18 大塚製薬株式会社 ピリミジン化合物の医薬用途
US10829457B2 (en) 2016-11-23 2020-11-10 Cv6 Therapeutics (Ni) Limited Nitrogen ring linked deoxyuridine triphosphatase inhibitors
US10858344B2 (en) 2016-11-23 2020-12-08 Cv6 Therapeutics (Ni) Limited Hydantoin containing deoxyuridine triphosphatase inhibitors
US10889563B2 (en) 2013-01-07 2021-01-12 University Of Southern California Deoxyuridine triphosphatase inhibitors
US11014924B2 (en) 2016-11-23 2021-05-25 Cv6 Therapeutics (Ni) Limited Hydantoin containing deoxyuridine triphosphatase inhibitors
US11168059B2 (en) 2016-11-23 2021-11-09 Cv6 Therapeutics (Ni) Limited Amino sulfonyl compounds
US11174271B2 (en) 2016-11-23 2021-11-16 Cv6 Therapeutics (Ni) Limited 6-membered uracil isosteres
US11198677B2 (en) 2015-07-08 2021-12-14 University Of Southern California Deoxyuridine triphosphatase inhibitors containing amino sulfonyl linkage
US12391674B2 (en) 2018-11-30 2025-08-19 Otsuka Pharmaceutical Co., Ltd. Heterocyclic compounds for the treatment of epilepsy
CN120965524A (zh) * 2025-10-21 2025-11-18 四川大学 一种(n,n-二甲基氨基)甲酸-4,5-二甲氧基-2-[(1e)-3-甲氧基-丙烯基]苯基酯化合物及其制备方法和应用

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JPS60243017A (ja) * 1984-05-16 1985-12-03 Kyowa Hakko Kogyo Co Ltd 抗けいれん組成物
JPS61236724A (ja) * 1985-04-13 1986-10-22 Kyowa Hakko Kogyo Co Ltd 抗けいれん組成物
CA2444148A1 (fr) * 2001-04-11 2002-10-24 Queen's University At Kingston Composes de pyrimidine en tant qu'agents anti-ictogeniques et/ou anti-epileptiques

Cited By (60)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8835426B2 (en) 2007-02-26 2014-09-16 Vitae Pharmaceuticals, Inc. Cyclic urea and carbamate inhibitors of 11β-hydroxysteroid dehydrogenase 1
US8329897B2 (en) 2007-07-26 2012-12-11 Vitae Pharmaceuticals, Inc. Synthesis of inhibitors of 11β-hydroxysteroid dehydrogenase type 1
US8575156B2 (en) 2007-07-26 2013-11-05 Vitae Pharmaceuticals, Inc. Cyclic inhibitors of 11β-hydroxysteroid dehydrogenase 1
US9079861B2 (en) 2007-11-07 2015-07-14 Vitae Pharmaceuticals, Inc. Cyclic urea inhibitors of 11β-hydroxysteroid dehydrogenase 1
US8440658B2 (en) 2007-12-11 2013-05-14 Vitae Pharmaceuticals, Inc. Cyclic urea inhibitors of 11β-hydroxysteroid dehydrogenase 1
US8748444B2 (en) 2007-12-11 2014-06-10 Vitae Pharmaceuticals, Inc. Cyclic urea inhibitors of 11β-hydroxysteroid dehydrogenase 1
US8680281B2 (en) 2008-01-07 2014-03-25 Vitae Pharmaceuticals, Inc. Lactam inhibitors of 11-β-hydroxysteroid dehydrogenase 1
US8592409B2 (en) 2008-01-24 2013-11-26 Vitae Pharmaceuticals, Inc. Cyclic carbazate and semicarbazide inhibitors of 11β-hydroxysteroid dehydrogenase 1
US8202857B2 (en) 2008-02-11 2012-06-19 Vitae Pharmaceuticals, Inc. 1,3-oxazepan-2-one and 1,3-diazepan-2-one inhibitors of 11β-hydroxysteroid dehydrogenase 1
US8598160B2 (en) 2008-02-15 2013-12-03 Vitae Pharmaceuticals, Inc. Cycloalkyl lactame derivatives as inhibitors of 11-beta-hydroxysteroid dehydrogenase 1
US8592410B2 (en) 2008-05-01 2013-11-26 Vitae Pharmaceuticals, Inc. Cyclic inhibitors of 11BETA-hydroxysteroid dehydrogenase 1
US8242111B2 (en) 2008-05-01 2012-08-14 Vitae Pharmaceuticals, Inc. Cyclic inhibitors of 11β-hydroxysteroid dehydrogenase 1
US8673899B2 (en) 2008-05-01 2014-03-18 Vitae Pharmaceuticals, Inc. Cyclic inhibitors of 11beta-hydroxysteroid dehydrogenase 1
US8569292B2 (en) 2008-05-01 2013-10-29 Vitae Pharmaceuticals, Inc. Cyclic inhibitors of 11β-hydroxysteroid dehydrogenase 1
US8138178B2 (en) 2008-05-01 2012-03-20 Vitae Pharmaceuticals, Inc. Cyclic inhibitors of 11beta-hydroxysteroid dehydrogenase 1
US8114868B2 (en) 2008-07-25 2012-02-14 Boehringer Ingelheim International Gmbh Cyclic inhibitors of 11β-hydroxysteroid dehydrogenase 1
US8846668B2 (en) 2008-07-25 2014-09-30 Vitae Pharmaceuticals, Inc. Inhibitors of 11beta-hydroxysteroid dehydrogenase 1
US8754076B2 (en) 2008-07-25 2014-06-17 Vitae Pharmaceuticals, Inc./Boehringer-Ingelheim Cyclic inhibitors of 11beta-hydroxysteroid dehydrogenase 1
US8637505B2 (en) 2009-02-04 2014-01-28 Boehringer Ingelheim International Gmbh Cyclic inhibitors of 11beta-hydroxysteroid dehydrogenase 1
US8680093B2 (en) 2009-04-30 2014-03-25 Vitae Pharmaceuticals, Inc. Cyclic inhibitors of 11beta-hydroxysteroid dehydrogenase 1
US8927539B2 (en) 2009-06-11 2015-01-06 Vitae Pharmaceuticals, Inc. Cyclic inhibitors of 11β-hydroxysteroid dehydrogenase 1 based on the 1,3-oxazinan-2-one structure
US8883778B2 (en) 2009-07-01 2014-11-11 Vitae Pharmaceuticals, Inc. Cyclic inhibitors of 11 beta-hydroxysteroid dehydrogenase 1
US9090605B2 (en) 2010-06-16 2015-07-28 Vitae Pharmaceuticals, Inc. Substituted 5-,6- and 7-membered heterocycles, medicaments containing such compounds, and their use
US8933072B2 (en) 2010-06-16 2015-01-13 Vitae Pharmaceuticals, Inc. Substituted 5-,6- and 7-membered heterocycles, medicaments containing such compounds, and their use
US8765744B2 (en) 2010-06-25 2014-07-01 Boehringer Ingelheim International Gmbh Azaspirohexanones
US8846613B2 (en) 2010-11-02 2014-09-30 Boehringer Ingelheim International Gmbh Pharmaceutical combinations for the treatment of metabolic disorders
US10889563B2 (en) 2013-01-07 2021-01-12 University Of Southern California Deoxyuridine triphosphatase inhibitors
US12098133B2 (en) 2015-07-08 2024-09-24 Cv6 Therapeutics (Ni) Limited Hydantoin containing deoxyuridine triphosphatase inhibitors
US11584723B2 (en) 2015-07-08 2023-02-21 Cv6 Therapeutics (Ni) Limited Hydantoin containing deoxyuridine triphosphatase inhibitors
US11479531B2 (en) 2015-07-08 2022-10-25 University Of Southern California Deoxyuridine triphosphatase inhibitors
US11198677B2 (en) 2015-07-08 2021-12-14 University Of Southern California Deoxyuridine triphosphatase inhibitors containing amino sulfonyl linkage
US10544105B2 (en) 2015-07-08 2020-01-28 Cv6 Therapeutics (Ni) Limited Deoxyuridine triphosphatase inhibitors containing cyclopropano linkage
US11124485B2 (en) 2015-07-08 2021-09-21 Cv6 Therapeutics (Ni) Limited Deoxyuridine triphosphatase inhibitors containing cyclopropano linkage
US10562860B2 (en) 2015-07-08 2020-02-18 Cv6 Therapeutics (Ni) Limited Hydantoin containing deoxyuridine triphosphatase inhibitors
US10570098B2 (en) 2015-07-08 2020-02-25 Cv6 Therapeutics (Ni) Limited Hydantoin containing deoxyuridine triphosphatase inhibitors
US10577321B2 (en) 2015-07-08 2020-03-03 University Of Southern California Deoxyuridine triphosphatase inhibitors
US11104649B2 (en) 2015-07-08 2021-08-31 Cv6 Therapeutics (Ni) Limited Hydantoin containing deoxyuridine triphosphatase inhibitors
US11174271B2 (en) 2016-11-23 2021-11-16 Cv6 Therapeutics (Ni) Limited 6-membered uracil isosteres
US11168059B2 (en) 2016-11-23 2021-11-09 Cv6 Therapeutics (Ni) Limited Amino sulfonyl compounds
US10858344B2 (en) 2016-11-23 2020-12-08 Cv6 Therapeutics (Ni) Limited Hydantoin containing deoxyuridine triphosphatase inhibitors
US11014924B2 (en) 2016-11-23 2021-05-25 Cv6 Therapeutics (Ni) Limited Hydantoin containing deoxyuridine triphosphatase inhibitors
US11518746B2 (en) 2016-11-23 2022-12-06 Cv6 Therapeutics (Ni) Limited Nitrogen ring linked deoxyuridine triphosphatase inhibitors
US10829457B2 (en) 2016-11-23 2020-11-10 Cv6 Therapeutics (Ni) Limited Nitrogen ring linked deoxyuridine triphosphatase inhibitors
WO2018128720A1 (fr) * 2017-01-05 2018-07-12 Cv6 Therapeutics (Ni) Limited Composés contenant de l'uracile
US11247984B2 (en) 2017-01-05 2022-02-15 Cv6 Therapeutics (Ni) Limited Uracil containing compounds
KR20200011962A (ko) 2017-05-31 2020-02-04 오츠카 세이야쿠 가부시키가이샤 피리미딘 화합물
IL270579B1 (en) * 2017-05-31 2023-04-01 Otsuka Pharma Co Ltd A pyrimidine compound
CN110603248A (zh) * 2017-05-31 2019-12-20 大塚制药株式会社 嘧啶化合物
EA038907B1 (ru) * 2017-05-31 2021-11-08 Оцука Фармасьютикал Ко., Лтд. Пиримидиновое соединение
WO2018221667A1 (fr) 2017-05-31 2018-12-06 Otsuka Pharmaceutical Co., Ltd. Composé de pyrimidine
KR20250065436A (ko) 2017-05-31 2025-05-12 오츠카 세이야쿠 가부시키가이샤 피리미딘 화합물
WO2018220762A1 (fr) * 2017-05-31 2018-12-06 大塚製薬株式会社 Composé de pyrimidine
JP2020503334A (ja) * 2017-05-31 2020-01-30 大塚製薬株式会社 ピリミジン化合物
CN110603248B (zh) * 2017-05-31 2023-07-04 大塚制药株式会社 嘧啶化合物
IL270579B2 (en) * 2017-05-31 2023-08-01 Otsuka Pharma Co Ltd A pyrimidine compound
KR20240116588A (ko) 2017-05-31 2024-07-29 오츠카 세이야쿠 가부시키가이샤 피리미딘 화합물
US10800758B2 (en) 2017-05-31 2020-10-13 Otsuka Pharmaceutical Co., Ltd. Pyrimidine compound
JP2020094045A (ja) * 2018-11-30 2020-06-18 大塚製薬株式会社 ピリミジン化合物の医薬用途
US12391674B2 (en) 2018-11-30 2025-08-19 Otsuka Pharmaceutical Co., Ltd. Heterocyclic compounds for the treatment of epilepsy
CN120965524A (zh) * 2025-10-21 2025-11-18 四川大学 一种(n,n-二甲基氨基)甲酸-4,5-二甲氧基-2-[(1e)-3-甲氧基-丙烯基]苯基酯化合物及其制备方法和应用

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