WO1998013044A1 - Compositions pharmaceutiques et methodes de traitement de troubles d'ordre compulsionnel a l'aide d'un inhibiteur de la naaladase - Google Patents

Compositions pharmaceutiques et methodes de traitement de troubles d'ordre compulsionnel a l'aide d'un inhibiteur de la naaladase Download PDF

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Publication number
WO1998013044A1
WO1998013044A1 PCT/US1997/014417 US9714417W WO9813044A1 WO 1998013044 A1 WO1998013044 A1 WO 1998013044A1 US 9714417 W US9714417 W US 9714417W WO 9813044 A1 WO9813044 A1 WO 9813044A1
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Prior art keywords
pentanedioic acid
methyl
straight
branched chain
acid
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PCT/US1997/014417
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English (en)
Inventor
Barbara S. Slusher
Paul F. Jackson
Kevin L. Tays
Keith M. Maclin
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Guilford Pharmaceuticals Inc.
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Publication date
Priority claimed from US08/718,703 external-priority patent/US5824662A/en
Priority claimed from US08/775,586 external-priority patent/US5795877A/en
Priority claimed from US08/778,733 external-priority patent/US5863536A/en
Priority claimed from US08/825,997 external-priority patent/US5962521A/en
Priority claimed from US08/835,572 external-priority patent/US5902817A/en
Priority claimed from US08/842,360 external-priority patent/US6054444A/en
Priority claimed from US08/858,985 external-priority patent/US6025344A/en
Priority claimed from US08/863,624 external-priority patent/US6046180A/en
Priority claimed from US08/884,479 external-priority patent/US6017903A/en
Priority to JP51563698A priority Critical patent/JP2002514185A/ja
Priority to CA002264158A priority patent/CA2264158A1/fr
Priority to AU41518/97A priority patent/AU4151897A/en
Priority to EP97939427A priority patent/EP0949922A1/fr
Application filed by Guilford Pharmaceuticals Inc. filed Critical Guilford Pharmaceuticals Inc.
Publication of WO1998013044A1 publication Critical patent/WO1998013044A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/66—Phosphorus compounds
    • A61K31/661—Phosphorus acids or esters thereof not having P—C bonds, e.g. fosfosal, dichlorvos, malathion or mevinphos
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/194—Carboxylic acids, e.g. valproic acid having two or more carboxyl groups, e.g. succinic, maleic or phthalic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/66—Phosphorus compounds
    • A61K31/665—Phosphorus compounds having oxygen as a ring hetero atom, e.g. fosfomycin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/66—Phosphorus compounds
    • A61K31/675—Phosphorus compounds having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/05—Dipeptides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/06—Tripeptides
    • 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
    • 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
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
    • 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
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
    • A61P25/32—Alcohol-abuse
    • 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
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
    • A61P25/34—Tobacco-abuse
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/28—Phosphorus compounds with one or more P—C bonds
    • C07F9/30—Phosphinic acids [R2P(=O)(OH)]; Thiophosphinic acids ; [R2P(=X1)(X2H) (X1, X2 are each independently O, S or Se)]
    • C07F9/301—Acyclic saturated acids which can have further substituents on alkyl
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/28—Phosphorus compounds with one or more P—C bonds
    • C07F9/38—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)]
    • C07F9/3804—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)] not used, see subgroups
    • C07F9/3808—Acyclic saturated acids which can have further substituents on alkyl
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/28—Phosphorus compounds with one or more P—C bonds
    • C07F9/38—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)]
    • C07F9/3804—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)] not used, see subgroups
    • C07F9/3826—Acyclic unsaturated acids

Definitions

  • the present invention relates to a pharmaceutical composition and a method for treating a compulsive disorder using a NAALADase inhibitor.
  • Glutamate serves as the predominant excitatory neurotransmitter in the central nervous system (CNS) . Neurons release glutamate in great quantities when they are deprived of oxygen, as may occur during an ischemic brain insult such as a stroke or a heart attack. This excess release of glutamate m turn causes over- stimulation (excitotoxicity) of N-methyl-D-aspartate (NMDA) , AMPA, Kainate and MGR receptors. When glutamate binds to these receptors, ion channels in the receptors open, permitting flows of ions across their cell membranes, e.g., Ca 2* and Na * into the cells and K + out of the cells.
  • ethanol neurophysiological and pathological effects of ethanol have been found to be mediated through the glutamatergic system. Specifically, acute exposure to ethanol disrupts glutamatergic neurotransmission by inhibiting ion flow through channels in glutamate receptors, whereas chronic exposure up-regulates the number of glutamate receptors and thereby increases ion flow. Acute withdrawal from ethanol results in hyperexcitability and seizures in the presence of up- regulated channels, thereby making postsynaptic neurons vulnerable to excitotoxic damage.
  • NAALADase Inhibitors NAAG and NAALADase have been implicated in several human and animal pathological conditions. For example, it has been demonstrated that intra-hippocampal injections of NAAG elicit prolonged seizure activity. More recently, it was reported that rats genetically prone to epileptic seizures have a persistent increase in their basal level of NAALADase activity. These observations support the hypothesis that increased availability of synaptic glutamate elevates seizure susceptibility, and suggest that NAALADase inhibitors may provide anti-epileptic activity.
  • NAAG and NAALADase have also been implicated in the pathogenesis of ALS and in the pathologically similar animal disease called Hereditary Canine Spinal Muscular Atrophy (HCSMA) . It has been shown that concentrations of NAAG and its metabolites -- NAA, glutamate and aspartate -- are elevated two- to three- fold in the cerebrospmal fluid of ALS patients and HCSMA dogs. Additionally, NAALADase activity is significantly increased (two- to three-fold) in post-mortem spinal cord tissue from ALS patients and HCSMA dogs. As such, NAALADase inhibitors may be clinically useful in curbing the progression of ALS if increased metabolism of NAAG is responsible for the alterations of CSF levels of these acidic ammo acids and peptides.
  • HCSMA Hereditary Canine Spinal Muscular Atrophy
  • NAALADase inhibitors could be useful m treating glutamate abnormalities.
  • the results of studies conducted by the inventors confirm that NAALADase inhibitors are effective in treating glutamate abnormalities, particularly stroke, Parkinson's Disease, Amyotrophic Lateral Sclerosis (ALS) , spinal cord injury, alcoholism and nicotine dependence.
  • ALS Amyotrophic Lateral Sclerosis
  • NAALADase inhibitors While a few NAALADase inhibitors have been identified, they have only been used in non-clinical research. Examples of such inhibitors include general metallopeptidase inhibitors such as o-phenanthrolme, metal chelators such as EGTA and EDTA, and peptide analogs such as quisqualic acid and ⁇ -NAAG. Accordingly, a need exists for new NAALADase inhibitors, as well as pharmaceutical compositions and methods using such new and known NAALADase inhibitors to treat glutamate abnormalities .
  • general metallopeptidase inhibitors such as o-phenanthrolme
  • metal chelators such as EGTA and EDTA
  • peptide analogs such as quisqualic acid and ⁇ -NAAG. Accordingly, a need exists for new NAALADase inhibitors, as well as pharmaceutical compositions and methods using such new and known NAALADase inhibitors to treat glutamate abnormalities .
  • the present invention further relates to a method of treating a compulsive disorder, comprising administering an effective amount of a NAALADase inhibitor to a patient in need thereof.
  • FIG. 1 is a bar graph plotting in vi tro toxicity of ischemic insult (potassium cyanide and 2 -deoxyglucose) against various doses of 2- (phosphonomethyl) pentanedioic acid with which cortical cell cultures were treated.
  • ischemic insult potassium cyanide and 2 -deoxyglucose
  • FIG. 2 is a bar graph plotting in vi tro toxicity against various doses of NAAG to which cortical cell cultures were exposed.
  • FIG. 3 is a bar graph plotting in vi tro toxicity following treatment with 2- (phosphonomethyl ) pentanedioic acid, against various doses of NAAG to which cortical cell cultures were exposed.
  • FIG. 4 is a bar graph plotting in vi tro toxicity of ischemic insult against various times at which cortical cell cultures were treated with 2- (phosphonomethyl) - pentanedioic acid.
  • FIG. 5 is a bar graph plotting in vivo cortical injury volume against various doses of 2-
  • FIG. 6 is a bar graph plotting in vivo total brain infarct volume of rats against various times at which the rats are treated with 2 - (phosphonomethyl) pentanedioic acid after sustaining middle cerebral artery occlusion.
  • FIG. 7 is a bar graph plotting in vi vo extracellular glutamate increases in the striatum of rats treated with a vehicle or 2 - (phosphonomethyl ) pentanedioic acid after sustaining middle cerebral artery occlusion.
  • FIG. 8 is a bar graph plotting in vivo extracellular glutamate increases in the parietal cortex of rats treated with a vehicle or 2 - (phosphonomethyl) pentanedioic acid after sustaining middle cerebral artery occlusion.
  • FIG. 9 is a bar graph plotting in vivo extracellular glutamate increases in the frontal cortex of rats treated with a vehicle or 2- (phosphonomethyl) entanedioic acid after sustaining middle cerebral artery occlusion.
  • FIG. 10(a) is a photomicrograph of mouse sciatic nerve treated with a vehicle following cryolesion.
  • FIG. 10(b) is a photomicrograph of mouse sciatic nerve treated with 2- (phosphonomethyl) pentanedioic acid following cryolesion.
  • FIG. 11 is a bar graph plotting percent striatal TH innervation density against the treatment of mice with vehicle alone, vehicle following MPTP, or 2- (phosphonomethyl) pentanedioic acid following MPTP.
  • FIG. 12 is a bar graph plotting the neurological function code against the treatment of rats with dynorphin A alone or 2- (phosphonomethyl) pentanedioic acid with dynorphin A.
  • FIG. 13 is a bar graph plotting the ChAT activity of rat spinal cord organotypic cultures against the treatment of the cultures with 2- (phosphonomethyl) - pentanedioic acid alone, threohydroxyaspartate (THA) alone, or THA with 2 - (phosphonomethyl) pentanedioic acid.
  • FIG. 14 is a bar graph plotting the ChAT activity of rat spinal cord organotypic cultures against various doses of 2- (phosphonomethyl) pentanedioic acid with which the cultures were treated in the presence of THA.
  • FIG. 15 is a bar graph plotting the ethanol intake of alcohol -preferring rats against various doses of 2-
  • FIG. 16 is a graph plotting the cumulative nicotine intake of rats during a 1 hour test session, before which the rats had been trained to self -administer nicotine and pretreated with a vehicle or 2 - (phosphonomethyl) - pentanedioic acid.
  • FIG. 17 is a graph plotting the cumulative food intake of rats during a 1 hour test session, before which the rats had been trained to self -administer nicotine and pretreated with a vehicle or 2 - (phosphonomethyl) - pentanedioic acid.
  • Attention Deficit Disorder refers to a disorder characterized by developmentally inappropriate inattention and impulsivity, with or without hyperactivity .
  • Inattention means a failure to finish tasks started, easy distractibility, seeming lack of attention, and difficulty concentrating on tasks requiring sustained attention.
  • Impulsivity means acting before thinking, difficulty taking turns, problems organizing work, and constant shifting from one activity to another.
  • Hyperactivity means difficulty staying seated and sitting still, and running or climbing excessively.
  • Compound 3 refers to 2- (phosphonomethyl) pentanedioic acid (PMPA) .
  • Compulsive disorder refers to any disorder characterized by irresistible impulsive behavior. Examples of compulsive disorders include without limitation drug dependence, eating disorders, pathological gambling, ADD and Tourette's syndrome.
  • Drug dependence refers to a psychologic addiction or a physical tolerance to a drug. Tolerance means a need to increase the dose progressively in order to produce the effect originally achieved by smaller amounts .
  • Eating disorder refers to compulsive overeating, obesity or severe obesity.
  • Obesity means body weight of 20% over standard height-weight tables.
  • Severe obesity means over 100% overweight.
  • glutamate abnormality refers to any disease, disorder or condition in which glutamate is implicated, including pathological conditions involving elevated levels of glutamate. Examples of glutamate abnormalities include epilepsy, stroke, Alzheimer's disease, Parkinson's Disease, Amyotrophic Lateral Sclerosis (ALS) , Huntington's Disease, schizophrenia, chronic pain, ischemia, neuronal insult and compulsive disorders.
  • glutamate modulator refers to any composition of matter which alone or in combination with another agent affects the level of glutamate in an animal .
  • Competitive, uncompetitive and non-competitive inhibition can be distinguished by the effects of an inhibitor on the reaction kinetics of an enzyme.
  • Competitive inhibition occurs when the inhibitor combines reversibly with the enzyme in such a way that it competes with a normal substrate for binding at the active site.
  • the affinity between the inhibitor and the enzyme may be measured by the inhibitor constant, K ⁇ , which is defined as :
  • [E] is the concentration of the enzyme
  • [I] is the concentration of the inhibitor
  • [El] is the concentration of the enzyme- inhibitor complex formed by the reaction of the enzyme with the inhibitor.
  • K 2 as used herein refers to the affinity between the inventive compounds and NAALADase.
  • IC 50 is a related term used to define the concentration or amount of a compound which is required to cause a 50% inhibition of the target enzyme.
  • Ischemia refers to localized tissue anemia due to obstruction of the inflow of arterial blood.
  • Global ischemia occurs when blood flow to the entire brain ceases for a period of time, such as may result from cardiac arrest.
  • Focal ischemia occurs when a portion of the brain is deprived of its normal blood supply, such as may result from thromboembolytic occlusion of a cerebral vessel, traumatic head injury, edema or brain tumor. Even if transient, both global and focal ischemia can produce widespread neuronal damage.
  • nerve tissue damage occurs over hours or even days following the onset of ischemia, some permanent nerve tissue damage may develop in the initial minutes following cessation of blood flow to the brain.
  • NAAG refers to N-acetyl-aspartyl -glutamate, an important peptide component of the brain, with levels comparable to the major inhibitor neurotransmitter gamma- aminobutyric acid (GABA) .
  • GABA neurotransmitter gamma- aminobutyric acid
  • NAAG is neuron-specific, present in synaptic vesicles and released upon neuronal stimulation in several systems presumed to be glutamatergic. Studies suggest that NAAG may function as a neurotransmitter and/or neuromodulator in the central nervous system, or as a precursor of the neurotransmitter glutamate .
  • NAALADase refers to N-acetylated ⁇ -linked acidic dipeptidase, a membrane-bound metallopeptidase which catabolizes NAAG to N-acetylaspartate (NAA) and glutamate:
  • NAALADase shows a high affinity for NAAG with a Km of 540 nM. If NAAG is a bioactive peptide, then NAALADase may serve to inactivate NAAG'S synaptic action. Alternatively, if NAAG functions as a precursor for glutamate, the primary function of NAALADase may be to regulate synaptic glutamate availability.
  • Neuronervous function refers to the various functions of the nervous system, which among other things provide an awareness of the internal and external environments of
  • Nerv insult refers to any damage to nervous tissue and any disability or death resulting therefrom.
  • the cause of nervous insult may be metabolic, toxic, neurotoxic, iatrogenic, thermal or chemical, and includes without limitation ischemia, hypoxia, cerebrovascular accident, trauma, surgery, pressure, mass effect, hemorrhage, radiation, vasospasm, neurodegenerative disease, neurodegenerative process, infection, Parkinson's disease, ALS, myelination/demyelination process, epilepsy, cognitive disorder, glutamate abnormality and secondary effects thereof.
  • ischemia hypoxia
  • cerebrovascular accident trauma, surgery, pressure, mass effect, hemorrhage, radiation, vasospasm
  • neurodegenerative disease neurodegenerative process
  • infection Parkinson's disease
  • ALS myelination/demyelination process
  • epilepsy cognitive disorder, glutamate abnormality and secondary effects thereof.
  • Nevous tissue refers to the various components that make up the nervous system, including without limitation neurons, neural support cells, glia, Schwann cells, vasculature contained within and supplying these structures, the central nervous system, the brain, the brain stem, the spinal cord, the junction of the central nervous system with the peripheral nervous system, the peripheral nervous system and allied structures.
  • Neuroprotective refers to the effect of reducing, arresting or ameliorating nervous insult, and protecting, resuscitating or reviving nervous tissue which has suffered nervous insult.
  • “Pathological gambling” is a condition characterized by a preoccupation with gambling. Similar to psychoactive substance abuse, its effects include development of tolerance with a need to gamble progressively larger amounts of money, withdrawal symptoms, and continued gambling despite severe negative effects on family and occupation.
  • “Pharmaceutically acceptable salt” refers to a salt of the inventive compounds which possesses the desired pharmacological activity and which is neither biologically nor otherwise undesirable.
  • the salt can be formed with inorganic acids such as acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate butyrate, citrate, camphorate, camphorsul onate, cyclopentanepropionate, digluconate, dodecylsul f ate , ethanesul f onate , fumarate, glucoheptanoate, glycerophosphate , hemisulfate heptanoate, hexanoate, hydrochloride hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, methanesulfonate, 2-naphthalenesulfonate, nicotmate, oxalate,
  • Examples of a base salt include ammonium salts, alkali metal salts such as sodium and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, salts with organic bases such as dicyclohexylamine salts, N-methyl- D-glucamine, and salts with amino acids such as arginine and lysine.
  • the basic nitrogen-containing groups can be quarternized with agents including lower alkyl halides such as methyl, ethyl, propyl and butyl chlorides, bromides and iodides; dialkyl sulfates such as dimethyl, diethyl, dibutyl and dia yl sulfates; long chain halides such as decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides; and aralkyl halides such as benzyl and phenethyl bromides .
  • lower alkyl halides such as methyl, ethyl, propyl and butyl chlorides, bromides and iodides
  • dialkyl sulfates such as dimethyl, diethyl, dibutyl and dia yl sulfates
  • long chain halides such as decyl, lauryl, myristyl and stearyl
  • Tourette's syndrome refers to an autosomal multiple tic disorder characterized by compulsive swearing, multiple muscle tics and loud noises. Tics are brief, rapid, involuntary movements that can be simple or complex; they are stereotyped and repetitive, but not rhythmic. Simple tics, such as eye blinking, often begin as nervous mannerisms. Complex tics often resemble fragments of normal behavior. “Treating” refers to:
  • treating refers to suppressing the psychologic addiction or physical tolerance to the drug of abuse, and relieving or preventing a withdrawal syndrome resulting from the drug dependence.
  • Withdrawal syndrome refers to a disorder characterized by untoward physical changes that occur when the drug is discontinued or when its effect is counteracted by a specific antagonist.
  • the present invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising:
  • composition may further comprise at least one additional therapeutic agent.
  • NAALADase is a metallopeptidase
  • useful NAALADase inhibitors for the pharmaceutical composition of the present invention include small molecule compounds with functional groups known to inhibit metallo- peptidases, such as hydroxyphosphinyl derivatives.
  • a preferred NAALADase inhibitor is a glutamate-derived hydroxyphosphinyl derivative, an acidic peptide analog, a conformationally restricted glutamate mimic or a mixture thereof .
  • a preferred acidic peptide analog is selected from the group consisting of Asp-Glu, Glu-Glu, Gly-Glu, gamma- Glu-Glu and Glu-Glu-Glu.
  • a preferred NAALADase inhibitor is a glutamate- derived hydroxyphosphinyl derivative of formula I :
  • Y is CR 3 R 4 , NR 5 or O;
  • Ri and R 5 are independently selected from the group consisting of hydrogen, straight or branched chain alkyl , C 2 -C 9 straight or branched chain alkenyl , C 3 -C 8 cycloalkyl , C 3 -C 7 cycloalkenyl and Ar, wherein said R j is unsubstituted or substituted with carboxy, C 3 -C 8 cycloalkyl, C 5 -C 7 cycloalkenyl, halo, hydroxy, nitro, trifluoromethyl, C 1 -C 6 straight or branched chain alkyl, C 2 -C 6 straight or branched chain alkenyl, Ci-Cg alkoxy, C 2 - C 9 alkenyloxy, phenoxy, benzyloxy, amino, Ar or a mixture thereof;
  • R 2 is selected from the group consisting of hydrogen, C j -C 9 straight or branched chain alkyl, C 2 -C 9 straight or branched chain alkenyl, C 3 -C B cycloalkyl, C 5 - C 7 cycloalkenyl and Ar, wherein said R 2 is unsubstituted or substituted with carboxy, C 3 -C 8 cycloalkyl, C-C 7 cycloalkenyl, halo, hydroxy, nitro, trifluoromethyl , C 3 - C 6 straight or branched chain alkyl, C 2 -C 6 straight or branched chain alkenyl, C j -Cg alkoxy, C 2 -C 6 alkenyloxy, phenoxy, benzyloxy, amino, Ar or a mixture thereof;
  • R 3 and R 4 are independently selected from the group consisting of hydrogen, Cj-Cj straight or branched chain alkyl, C 2 -C 6 straight or branched chain alkenyl, C 3 -C 8 cycloalkyl, C 5 -C 7 cycloalkenyl, Ar, halo and mixtures thereof;
  • Ar is selected from the group consisting of 1- naphthyl, 2 -naphthyl, 2-indolyl, 3-indolyl, 4-indolyl, 2- furyl, 3-furyl, tetrahydrofuranyl , tetrahydropyranyl , 2- thienyl, 3-thienyl, 2 -pyridyl, 3 -pyridyl, 4 -pyridyl, benzyl and phenyl, wherein said Ar is unsubstituted or substituted with halo, hydroxy, nitro, trifluoromethyl , C j -Cg straight or branched chain alkyl, C 2 -C 6 straight or branched chain alkenyl, C 1 -C 6 alkoxy, C 2 -C 6 alkenyloxy, phenoxy, benzyloxy, amino or a mixture thereof.
  • Y is CH 2 . More preferably, R 2 is substituted with
  • R- ⁇ is hydrogen, C j -C 4 straight or branched chain alkyl, C 2 -C 4 straight or branched chain alkenyl, C 3 -C 8 cycloalkyl, C b -C 7 cycloalkenyl, benzyl or phenyl, wherein said R ⁇ is unsubstituted or substituted with carboxy, C 3 -C cramp cycloalkyl, C 5 -C 7 cycloalkenyl, halo, hydroxy, nitro, trifluoromethyl , C x - C 6 straight or branched chain alkyl, C 2 -C 6 straight or branched chain alkenyl, C x -C 4 alkoxy, C 2 -C 4 alkenyloxy, phenoxy, benzyloxy, amino, benzyl, phenyl or mixtures thereof; and R 2 is C 1 -C 2 alkyl.
  • the glutamate-derived hydroxyphosphinyl derivative is selected from the group consisting of: 2- (phosphonomethyl) pentanedioic acid; 2- (phosphonomethyl) succinic acid;
  • R 2 is C 3 -C 9 alkyl
  • R l is 2- indolyl, 3-indolyl, 4-indolyl, 2-furyl, 3-furyl, tetrahydrofuranyl, tetrahydropyranyl , 2-thienyl, 3- thienyl, 2 -pyridyl, 3 -pyridyl, 4 -pyridyl or C 1 -C 4 straight or branched chain alkyl substituted with 2- indolyl, 3-indolyl, 4-indolyl, 2-furyl, 3-furyl, tetrahydrofuranyl, 2-thienyl, 3-thienyl, 2 -pyridyl, 3- pyridyl or 4 -pyridyl; or R x is 1 -naphthyl, 2 -naphthyl, or
  • Y is CH 2 and R 2 is selected from the group consisting of hydrogen, C 1 -C 9 straight or branched chain alkyl, C 2 -C 9 straight or branched chain alkenyl, C 3 -C 8 cycloalkyl, C 5 ⁇ C 1 cycloalkenyl, benzyl and phenyl, wherein said R 2 is unsubstituted or substituted with C 3 -C 8 cycloalkyl, C b -C 7 cycloalkenyl, C 3 -C 6 straight or branched chain alkyl, C 2 - C 6 straight or branched chain alkenyl, C x -C 4 alkoxy, phenyl or mixtures thereof .
  • R 1 is hydrogen, C x -C 4 straight or branched chain alkyl, C 2 -C 4 straight or branched chain alkenyl, C 3 -C 8 cycloalkyl, C 5 -C 7 cycloalkenyl, benzyl or phenyl, wherein said R ⁇ is unsubstituted or substituted with carboxy, C 3 -C 8 cycloalkyl, C 5 -C 7 cycloalkenyl, halo, hydroxy, nitro, trifluoromethyl , C- L -C 6 straight or branched chain alkyl, C 2 -C 6 straight or branched chain alkenyl, C 1 -C 1 alkoxy, C 2 -C 4 alkenyloxy, phenoxy, benzyloxy, amino, benzyl, phenyl or mixtures thereof.
  • the glutamate-derived hydroxyphosphinyl derivative is selected from the group consisting of:
  • R x and R 2 is 2 -indolyl, 3-indolyl, 4-indolyl, 2-furyl, 3-furyl, tetrahydrofuranyl, tetrahydropyranyl, 2 -thienyl, 3- thienyl, 2 -pyridyl, 3-pyridyl, 4 -pyridyl, or C ⁇ C, straight or branched chain alkyl substituted with 2- indolyl 3-indolyl, 4-indolyl, 2-furyl, 3-furyl, tetrahydrofuranyl, 2 -thienyl, 3-thienyl, 2 -pyridyl, 3-pyridyl or 4 -pyridyl; or R x is 1-n
  • Preferred compounds of these embodiments include: 3 - [ (2 -pyridyl) methylhydroxyphosphinyl] -2-phenylpropanoic acid; 3- [ (3 -pyridyl) methylhydroxyphosphinyl] -2-phenylpropanoic acid;
  • R 2 is preferably substituted with carboxy .
  • Exemplary compounds of this embodiment include: 2- [ [methylhydroxyphosphinyl] oxy] pentanedioic acid;
  • R 2 is selected from the group consisting of hydrogen, C x -C 9 straight or branched chain alkyl, C 2 -C 9 straight or branched chain alkenyl, C 3 -C 8 cycloalkyl, C 3 -C 7 cycloalkenyl, benzyl and phenyl, wherein said R 2 is unsubstituted or substituted with C 3 -C 8 cycloalkyl, C 3 -C 7 cycloalkenyl, straight or branched chain alkyl, C 2 -C 6 straight or branched chain alkenyl, C 1 -C 4 alkoxy, phenyl or mixtures thereof.
  • Exemplary compounds of this embodiment include: 2- [ [ (2 -pyridyl) methylhydroxyphosphinyl] oxy] -2-phenylethanoic acid; 2- [ [ (3 -pyridyl) methylhydroxyphosphinyl] oxy] -2-phenyl ethanoic acid;
  • R 2 is preferably substituted with carboxy .
  • R 2 is selected from the group consisting of hydrogen, Cj-Cg straight or branched chain alkyl, C 2 -C 9 straight or branched chain alkenyl, C 3 -C B cycloalkyl, C 5 -C 7 cycloalkenyl, benzyl and phenyl, wherein said R 2 is unsubstituted or substituted with C 3 -C 8 cycloalkyl, C 5 -C 7 cycloalkenyl, C j -C 8 straight or branched chain alkyl, C 2 -C 6 straight or branched chain alkenyl, C j -C 4 alkoxy, phenyl or mixtures thereof.
  • NAALADase inhibitor is a compound of formula II:
  • Y is CR j R 2 , NR 3 or 0;
  • R, R 1( R 2 and R 3 are independently selected from the group consisting of hydrogen, straight or branched chain alkyl, C 2 -C 9 straight or branched chain alkenyl, C 3 ⁇ C 8 cycloalkyl, C 5 -C 7 cycloalkenyl, Ar and mixtures thereof, wherein said R, R 3 , R and R 3 are independently unsubstituted or substituted with C 3 -C 8 cycloalkyl, C 3 -C 7 cycloalkenyl, halo, hydroxy, nitro, trifluoromethyl , C x - C 6 straight or branched chain alkyl, C 2 -C 6 straight or branched chain alkenyl, Cj-Cg alkoxy, C 2 -C 9 alkenyloxy, phenoxy, benzyloxy, ammo, Ar or a mixture thereof; and Ar is selected from the group consisting of 1- naphthyl, 2-naphthyl, 2-m
  • R is selected from the group consisting of hydrogen, C 1 -C 4 straight or branched chain alkyl, 4 -pyridyl, benzyl and phenyl, said R having one to three substituent (s) independently selected from the group consisting of hydrogen, C 3 -C ⁇ cycloalkyl, C 5 -C 7 cycloalkenyl, halo, hydroxy, nitro, trifluoromethyl , straight or branched chain alkyl, C 2 -C 6 straight or branched chain alkenyl, Cj-C 4 alkoxy, C 2 - C 4 alkenyloxy, phenoxy, benzyloxy, ammo, Ar and mixtures thereof.
  • the compound is selected from the group consisting of:
  • Another preferred NAALADase inhibitor is a compound of formula V:
  • X is selected from the group consisting of
  • VI VII VIII Y is CR j R 2 , NR 3 or O;
  • R, R 1( R 2 and R 3 are independently selected from the group consisting of hydrogen, C 1 -C 8 straight or branched chain alkyl, C 2 -C 9 straight or branched chain alkenyl, C 3 - C 8 cycloalkyl, C 5 -C 7 cycloalkenyl and Ar, wherein said R, Rj, R 2 and R 3 are independently unsubstituted or substituted with C 3 -C 8 cycloalkyl, C 5 -C, cycloalkenyl, halo, hydroxy, nitro, trifluoromethyl , C j -C 6 straight or branched chain alkyl, C 2 -C 6 straight or branched chain alkenyl, C x -C 9 alkoxy, C -C,j alkenyloxy, phenoxy, benzyloxy, amino, Ar or a mixture thereof; and
  • Ar is selected from the group consisting of 1- naphthyl, 2-naphthyl, 2-mdolyl, 3-mdolyl, 2-furyl, 3- furyl , 2 -thienyl, 3-thienyl, 2 -pyridyl, 3-pyridyl, 4- pyridyl, benzyl and phenyl, said Ar having one to three substituent (s) independently selected from the group consisting of hydrogen, halo, hydroxy, nitro, trifluoromethyl , C 3 -C 6 straight or branched chain alkyl, C 2 -C 6 straight or branched chain alkenyl, Cj-Cg alkoxy, C 2 - C 6 alkenyloxy, phenoxy, benzyloxy, amino and mixtures thereof.
  • R j , R 2 and R 3 is/are independently substituted with C 3 -C a cycloalkyl, C 5 -C 7 cycloalkenyl, hydroxy, halo, nitro, trifluoromethyl , straight or branched chain alkyl,
  • Y is CH 2 .
  • R is selected from the group consisting of hydrogen, C j -C,, straight or branched chain alkyl, 4 -pyridyl, benzyl and phenyl, said R having one to three substituent (s) independently selected from the group consisting of hydrogen, C 3 -C 8 cycloalkyl, C 5 -C 7 cycloalkenyl, halo, hydroxy, nitro, trifluoromethyl , C 1 - C 6 straight or branched chain alkyl, C 2 -C 6 straight or branched chain alkenyl, C,-C 4 alkoxy, C 2 - C 4 alkenyloxy, phenoxy, benzyloxy, ammo, Ar and mixtures thereof .
  • the compound is selected from the group consisting of:
  • Another preferred NAALADase inhibitor is a compound of formula IX :
  • Y is CR 3 R 4 , NR 5 or 0;
  • R 2 is selected from the group consisting of hydrogen, straight or branched chain alkyl, C 2 -C 9 straight or branched chain alkenyl, C 3 -C 8 cycloalkyl, C 3 - C 7 cycloalkenyl and Ar, wherein said R 2 is unsubstituted or substituted with carboxy, C 3 -C 8 cycloalkyl, C 5 -C 7 cycloalkenyl, halo, hydroxy, nitro, trifluoromethyl , C 3 - C 6 straight or branched chain alkyl, C 2 -C 6 straight or branched chain alkenyl, C 1 - C g alkoxy, C 2 -C 9 alkenyloxy, phenoxy, benzyloxy, amino, Ar or a mixture thereof;
  • R x , R 3 , R 4 and R 5 are independently selected from the group consisting of hydrogen, C x -C 9 straight or branched chain alkyl, C 2 -C 9 straight or branched chain alkenyl, C 3 - C 8 cycloalkyl, C 5 -C 7 cycloalkenyl and Ar, wherein said R, R 1# R 2 and R 3 are independently unsubstituted or substituted with C 3 -C 8 cycloalkyl, C 5 -C 7 cycloalkenyl, halo, hydroxy, nitro, trifluoromethyl , straight or branched chain alkyl, C 2 -C 6 straight or branched chain alkenyl, alkoxy, C 2 -C 9 alkenyloxy, phenoxy, benzyloxy, amino, Ar or a mixture thereof; and
  • Ar is selected from the group consisting of 1- naphthyl , 2-naphthyl, 2 -indolyl, 3-indolyl, 2-furyl, 3- furyl, 2 -thienyl, 3-thienyl, 2 -pyridyl, 3-pyridyl, 4- pyridyl, benzyl and phenyl, wherein said Ar has one to three substituent (s) independently selected from the group consisting of hydrogen, halo, hydroxy, nitro, trifluoromethyl , straight or branched chain alkyl,
  • Y is CH 2 .
  • the compound is preferably selected from the group consisting of : phosphonopropanoic acid;
  • R 2 is substituted with carboxy, the compound is selected from the group consisting of:
  • Another preferred NAALADase inhibitor is a compound of formula X:
  • R and R x are independently selected from the group consisting of hydrogen, C ⁇ -C 9 straight or branched chain alkyl or alkenyl group, C 3 -C 8 cycloalkyl, C 3 or C 5 cycloalkyl, C 5 -C 7 cycloalkenyl and Ar, wherein said R and R x are independently unsubstituted or substituted with C 3 -C a cycloalkyl, C 5 -C 7 cycloalkenyl, halo, hydroxy, nitro, trifluoromethyl, straight or branched chain alkyl, C 2 -C 6 straight or branched chain alkenyl, C j -Cc, alkoxy, C 2 -C 9 alkenyloxy, phenoxy, benzyloxy, ammo, Ar or a mixture thereof; and
  • Ar is selected from the group consisting of 1- napthyl , 2-napthyl, 2 -indolyl, 3 -indolyl, 4 -indolyl, 2- furyl, 3-furyl, tetrahydrofuranyl, tetrahydropyranyl, 2- thienyl, 3 -thienyl, 2 -pyridyl, 3 -pyridyl, 4 -pyridyl, benzyl and phenyl, wherein said Ar is unsubstituted or substituted with halo, hydroxy, nitro, trifluoromethyl ,
  • the compound is selected from the group consisting of:
  • N- [methylhydroxyphosphinyl] glutamic acid N- [ethylhydroxyphosphinyl] glutamic acid;
  • a final preferred NAALADase inhibitor is a compound of formula XI :
  • R is selected from the group consisting of hydrogen, Ci-Cg straight or branched chain alkyl, C 2 -C Conduct straight or branched chain alkenyl, C 3 -C 8 cycloalkyl, C 5 -C 7 cycloalkenyl, Ar and mixtures thereof, wherein said R is unsubstituted or substituted with C 3 -C 8 cycloalkyl, C 5 -C 7 cycloalkenyl, halo, hydroxy, nitro, trifluoromethyl , C 2 - C 6 straight or branched chain alkyl, C 2 -C 6 straight or branched chain alkenyl, C 3 -C 9 alkoxy, C 2 -C 9 alkenyloxy, phenoxy, benzyloxy, ammo, Ar or a mixture thereof;
  • Ar is selected from the group consisting of 1- napthyl, 2-napthyl, 2 -indolyl, 3 -indolyl, 2-furyl, 3- furyl, 2 -thienyl, 3 -thienyl, 2-, 3-, or 4 -pyridyl, or phenyl, having one to three substituents which are independently selected from the group consisting of hydrogen, halo, hydroxyl, nitro, trifluoromethyl , straight or branched alkyl or alkenyl, alkoxy or C - C 6 alkenyloxy, phenoxy, benzyloxy, and ammo.
  • the compound is selected from the group consisting of:
  • NAALADase inhibitors of formula I can be readily prepared by standard techniques of organic chemistry, utilizing the general synthetic pathways depicted below m Schemes I -IX.
  • Precursor compounds can be prepared by methods known in the art , such as those described by Jackson et al . , J “ . Med . Chem . , Vol. 39, No. 2, pp. 619- 622 (1996) and Froestl et al . , J. Med . Chem . , Vol. 38, pp. 3313-3331 (1995) .
  • Scheme IV and Scheme V show the starting material as a phosphinic acid derivative and the R group as any reasonable chemical substituent including without limitation the substituents listed in Scheme II and throughout the specification.
  • NAALADase inhibitors modulate levels of glutamate by acting on a storage form of glutamate which is hypothesized to be upstream from the effects mediated by the NMDA receptor.
  • the inventors have unexpectedly found that NAALADase inhibitors are effective in treating glutamate-related compulsive disorders.
  • the present invention further relates to a method of treating a compulsive disorder, comprising administering an effective amount of a NAALADase inhibitor to a patient in need thereof.
  • the compulsive disorder may be any disorder characterized by irresistible impulsive behavior.
  • Examples of compulsive disorders treatable by the methods of the present invention include drug dependence, eating disorders, pathological gambling, ADD and Tourette's syndrome .
  • the compulsive disorder is drug dependence.
  • CNS depressants opioid, synthetic narcotics, barbiturates, glutethimide , methyprylon, ethchlorvynol , methaqualone , alcohol
  • anxiolytics diazepam, chlordiazepoxide , alprazolam, oxazepam, temazepam
  • stimulants amphetamine, methamphetamine , cocaine
  • hallucinogens LSD, mescaline, peyote, marijuana
  • the drug dependence is alcohol, nicotine, heroin or cocaine dependence.
  • NAALADase inhibitors useful for the methods of the present invention are identified above in relation to pharmaceutical compositions.
  • the compounds may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally or via an implanted reservoir in dosage formulations containing conventional non-toxic pharmaceutically-acceptable carriers, adjuvants and vehicles.
  • parenteral as used herein includes subcutaneous, intravenous, intramuscular, intraperitoneal , intrathecal, intraventricular , intrasternal or intracranial injection and infusion techniques. Invasive techniques are preferred, particularly direct administration to damaged neuronal tissue .
  • the NAALADase inhibitors used in the methods of the present invention should readily penetrate the blood-brain barrier when peripherally administered.
  • Compounds which cannot penetrate the blood-brain barrier can be effectively administered by an intraventricular route .
  • the compounds may also be administered in the form of sterile injectable preparations, for example, as sterile injectable aqueous or oleaginous suspensions. These suspensions can be formulated according to techniques known in the art using suitable dispersing or wetting agents and suspending agents.
  • the sterile injectable preparations may also be sterile injectable solutions or suspensions in non-toxic parenterally- acceptable diluents or solvents, for example, as solutions in 1, 3-butanediol .
  • Suitable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution.
  • sterile fixed oils are conventionally employed as solvents or suspending mediums.
  • any bland fixed oil such as a synthetic mono- or di -glyceride may be employed.
  • Fatty acids such as oleic acid and its glyceride derivatives, including olive oil and castor oil, especially in their polyoxyethylated forms, are useful in the preparation of injectables.
  • These oil solutions or suspensions may also contain long- chain alcohol diluents or dispersants.
  • the compounds may be administered orally in the form of capsules, tablets, aqueous suspensions or solutions.
  • Tablets may contain carriers such as lactose and corn starch, and/or lubricating agents such as magnesium stearate.
  • Capsules may contain diluents including lactose and dried corn starch.
  • Aqueous suspensions may contain emulsifying and suspending agents combined with the active ingredient.
  • the oral dosage forms may further contain sweetening and/or flavoring and/or coloring agents.
  • the compounds may further be administered rectally in the form of suppositories. These compositions can be prepared by mixing the drug with suitable non-irritating excipients which are solid at room temperature, but liquid at rectal temperature such that they will melt in the rectum to release the drug. Such excipients include cocoa butter, beeswax and polyethylene glycols.
  • the compounds may be administered topically, especially when the conditions addressed for treatment involve areas or organs readily accessible by topical application, including neurological disorders of the eye, the skin or the lower intestinal tract.
  • the compounds can be formulated as micronized suspensions in isotonic, pH adjusted sterile saline or, preferably, as a solution in isotonic, pH adjusted sterile saline, either with or without a preservative such as benzylalkonium chloride.
  • the compounds may be formulated into ointments, such as petrolatum.
  • the compounds can be formulated into suitable ointments containing the compounds suspended or dissolved in, for example, mixtures with one or more of the following: mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene polyoxypropylene compound, emulsifying wax and water.
  • the compounds can be formulated into suitable lotions or creams containing the active compound suspended or dissolved in, for example, a mixture of one or more of the following: mineral oil, sorbitan monostearate, polysorbate 60, cetyl ester wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water.
  • Topical application to the lower intestinal tract can be effected in rectal suppository formulations (see above) or in suitable enema formulations.
  • NAALADase inhibitors used in the methods of the present invention may be administered by a single dose, multiple discrete doses or continuous infusion. Since the compounds are small, easily diffusible and relatively stable, they are well suited to continuous infusion. Pump means, particularly subcutaneous pump means, are preferred for continuous infusion.
  • Dose levels on the order of about 0.1 mg to about 10,000 mg of the active ingredient compound are useful in the treatment of the above conditions, with preferred levels being about 0.1 mg to about 1,000 mg .
  • the specific dose level for any particular patient will vary depending upon a variety of factors, including the activity of the specific compound employed; the age, body weight, general health, sex and diet of the patient; the time of administration; the rate of excretion; drug combination; the severity of the particular disease being treated; and the form of administration.
  • vi tro dosage-effect results provide useful guidance on the proper doses for patient administration. Studies in animal models are also helpful. The considerations for determining the proper dose levels are well known in the art .
  • the NAALADase inhibitors are administered in lyophilized form.
  • 1 to 100 mg of a NAALADase inhibitor may be lyophilized in individual vials, together with a carrier and a buffer, such as mannitol and sodium phosphate .
  • the compound may be reconstituted in the vials with bacteriostatic water before administration.
  • the NAALADase inhibitors used in the methods of the present invention may be administered in combination with one or more therapeutic agents. Specific dose levels for these agents will depend upon considerations such as those identified above for the NAALADase inhibitors.
  • any administration regimen regulating the timing and sequence of drug delivery can be used and repeated as necessary to effect treatment.
  • Such regimen may include pretreatment and/or co-administration with additional therapeutic agents .
  • NAALADase inhibitors should be administered to the affected cells as soon as possible.
  • the compounds should be administered before the expected nervous insult.
  • Such situations of increased likelihood of nervous insult include surgery (cartoid endarterectomy, cardiac, vascular, aortic, orthopedic); endovascular procedures such as arterial catherization (cartoid, vertebral, aortic, cardia, renal, spinal, Adamkiewicz) ; injections of embolic agents; coils or balloons for hemostasis; interruptions of vascularity for treatment of brain lesions; and predisposing medical conditions such as crescendo transient ischemic attacks, emboli and sequential strokes.
  • the NAALADase inhibitors can be co-administered with one or more therapeutic agents, preferably agents which can reduce the risk of stroke (such as aspirin) , and more preferably agents which can reduce the risk of a second ischemic event (such as ticlopidine) .
  • the NAALADase inhibitors can be co-administered with one or more therapeutic agents either (i) together in a single formulation, or (ii) separately in individual formulations designed for optimal release rates of their respective active agent.
  • Each formulation may contain from about 0.01% to about 99.99% by weight, preferably from about 3.5% to about 60% by weight, of a NAALADase inhibitor, as well as one or more pharmaceutical excipients, such as wetting, emulsifying and pH buffering agents.
  • mice 500 mg/kg body weight. The mice were subsequently observed two times per day for 5 consecutive days. The survival rate at each dose level is provided below in
  • 2- (phosphonomethyl) succinic acid exhibits much lower NAALADase inhibiting activity, suggesting that a glutamate analog attached to the phosphonic acid contributes to its NAALADase inhibiting activity.
  • Neuroprotective effect of each tested compound is provided below in TABLE III (a) .
  • Neuroprotective effect is expressed as EC 50 , the concentration which is required to cause a 50% reduction in glutamate toxicity following an ischemic insult.
  • the results show that toxicity increased as the concentration of NAAG increased.
  • the toxicity is attributed to the release of glutamate by NAAG when cleaved by NAALADase.
  • NAAG To examine the effect of NAALADase inhibitors on in vi tro toxicity of NAAG, cortical cell cultures were treated with 2 - (phosphonomethyl) pentanedioic acid (1 ⁇ M) during exposure to NAAG and for one hour thereafter. The toxicity measurement for each concentration of NAAG is provided below in TABLE V and graphically presented in FIG. 3.
  • Dissociated cortical cell cultures are prepared using the papam-dissociation method of Heuttner and Baughman (1986) as modified by Murphy and Baraban (1990) . See TABLE VII for the Dissociated Culture Protocol as used herein. Fetuses of embryonic day 17 are removed from timed pregnancy rats (Harlan Sprague Dawley) . The cortex is rapidly dissected out Dulbecco's phosphate- buffered salme, stripped of menmges, and incubated m a papain solution for 15 minutes at 37° C. The tissue is then mechanically triturated and pelleted at 500 g (1000- 2000 rpm on swinging bucket Beckman) .
  • the pellet is resuspended in a DNAase solution, triturated with a 10 ml pipette xl5-20, layered over a "10 x 10" solution containing albumin and trypsm inhibitor (see TABLE VII for an example of a "10 x 10" solution), repelleted, and resuspended in a plating medium containing 10% fetal bovine serum (HyClone A-llll-L), 5% heat -inactivated Equine serum (HyClone A-3311-L) , and 84% modified Earle's basal medium (MEM) (Gibco 51200 020) with high glucose
  • Each 24-well plate is pretreated with poly-D-lysme (0.5 ml/well of 10 ⁇ g/ml) for 1 h and rinsed with water before plating.
  • Cultures are plated at 2.5 x 10 6 cells/ml with each well of a 24 well plate receiving 500 ⁇ l/well.
  • 35 mm dishes can be plated at 2 ml/dish, 6 well plates at 2 ml/well, or 12 well plates at 1 ml/well.
  • Cysteine (C-8277) ; DNAase, 5 ml 25 ml dissoc. EBSS; 4.5 ml dissoc. EBSS; 250 ⁇ l Papain stock 500 ⁇ l "10 and 10" stock; (Worthington LS003126) ; 50 ⁇ l DNAase stock. place in 37°C waterbath until clear. "10 and 10" , 5 ml
  • Brain removal Penetrate skull and skin with fine forceps at lambda. Pull back to open posterior fossa. Then move forceps anteriorly to separate sagittal suture. Brain can be removed by scooping back from olfactory bulbs under the brain.
  • NAAG concentrations range from 3 ⁇ M to 3 mM, and include 3 ⁇ M, 10 ⁇ M, 30 ⁇ M, 100 ⁇ M, 300 ⁇ M, 1 mM, and 3 mM.
  • the cells are washed once with HEPES buffered saline solution and then replaced with serum free modified Earle's basal medium. The cultures are then returned to the CO ? incubator for 24 hour recovery. d. Lactate Dehydrogenase Assay
  • LDH lactate dehydrogenase
  • a measurement of the potency of each compound tested is made by measuring the percentage of LDH release into the growth media after exposure to NAAG/ischemia plus NAALADase inhibitor or NAAG/ischemia plus salme (control) . Since high concentrations of glutamate may be toxic to cells in certain circumstances, measurement of glutamate toxicity is observed using LDH as a standard measurement technique .
  • a colony of SHRSP rats is bred at Johns Hopkins School of Medicine from three pairs of male and female rats obtained from the National Institutes of Health (Laboratory, Sciences Section, Veterinary Resources Program, National Center for Research Resources, Bethesda, MD) . All rats are kept in a virus -free environment and maintained on regular diet (NIH 31, Zeigler Bros, Inc.) with water ad libitum. All groups of rats are allowed to eat and drink water until the morning of the experiment .
  • Transient occlusion of the middle cerebral artery is induced by advancing a 4-0 surgical nylon suture into the internal carotid artery (ICA) to block the origin of the MCA (Koizumi, 1986; Longa, 1989; Chen, 1992) .
  • the rats are anesthetized with 4% halothane, and maintained with 1.0% to 1.5% halothane in air enriched oxygen using a face mask. Rectal temperature is maintained at 37.0 ⁇ 0.5°C throughout the surgical procedure using a heating lamp.
  • the right femoral artery is cannulated for measuring blood gases (pH, oxygen tension [P0 2 ] , carbon dioxide tension [PC0 2 ] ) before and during ischemia, for monitoring blood pressure during the surgery.
  • the right common carotid artery (CCA) is exposed through a midline incision; a self -retraining retractor is positioned between the digastric and mastoid muscles, and the omohyoid muscle is divided.
  • the right external carotid artery (ECA) is dissected and ligated.
  • the occipital artery branch of the ECA is then isolated and coagulated.
  • the right internal carotid artery (ICA) is isolated until the pterygopalatine artery is exposed, and carefully separated from the adjacent vagus nerve.
  • the pterygopalatine artery is ligated with 4-0 silk suture close to its origin.
  • a 4-0 silk suture to prevent bleeding from a puncture site through which a 2.5 cm length of 4-0 monofilament nylon suture (Ethilon) , its tip rounded by heating near a electric cautery, is introduced into the ICA lumen.
  • a 6- 0 silk suture is tightened around the in raluminal nylon suture at the bifurcation to prevent bleeding, and the stretched sutures at the CCA and the ICA are released.
  • the nylon suture is then gently advanced as far as 20 mm.
  • Anesthesia is terminated after 10 minutes of MCA occlusion in both groups, and the rats were awakened 5 minutes thereafter. After 2 hours of ischemia, anesthesia is reanesthetized, and reperfusion is performed by withdrawing the intraluminal nylon suture until the distal tip became visible at the origin of the ICA.
  • Arterial pH and PaC0 2 , and partial pressure of oxygen (Pa0 2 ) are measured with a self -calibrating Radiometer electrode system (ABL 3; Copenhagen, Denmark) .
  • Hemoglobin and arterial oxygen content are measured with a hemoximeter (Radiometer, Model 0SM3 ; Copenhagen, Denmark) .
  • Blood glucose is measured with a glucose analyzer (model 2300A, Yellow Springs Instruments, Yellow Springs, OH) .
  • each group is exposed to 2 hours of right MCA occlusion and 22 hours of reperfusion. All variables but the rectal temperature are measured at baseline, at 15 minutes and 45 minutes of right MCA occlusion. The rectal temperature is measured at baseline, at 0 and 15 min of MCA occlusion, and at 0 and 22 hours of reperfusion.
  • the total infarct volume for each group of rats is graphically presented in FIG. 6.
  • Rats treated with 2- (phosphonomethyl) pentanedioic acid either before or after the ischemic insult exhibited significantly lower mean total brain infarct volumes of 122 + 26 mm 3 (p 0.003 vs. vehicle) for 20 minute pre-treatment, 208 ⁇ 40 mm 3 (p
  • Sprague-Dawley rats Male Sprague-Dawley rats (260-320 g) were used. Prior to the experiment, the rats were individually housed and allowed free access to food and water. Each rat received two surgeries: jugular vein cannulation for IV infusion and MCAO. During surgeries, the rat was anesthetized with 2% halothane delivered in oxygen via an inhalation mask. The body temperature was monitored and regulated at normothermic level using a homeothermic heating system. First, a PE-50 polyethylene catheter was inserted into the right jugular vein. One hour later, the rat was reanesthetized for MCAO surgery. The MCAO was achieved using the endovascular suture method described by Long et al . , Stroke, Vol.
  • the rats were dialyzed with perfusion fluid (125 mM NaCl, 2.5 mM KC1, 1.18 mM MgCl 2 and 1.26 mM CaCl ? ) at a rate of 2.5 ⁇ l/min. Following a 60 minute stabilization period, dialysis samples were collected every 20 minutes. After collecting 3 baseline samples, the rats were anaesthetized with halothane and subjected to temporary ischemia using the filament method of MCAO (Britton et al . , Life Sciences, Vol. 60, No. 20, pp. 1729-1740 (1997)). In brief, the right external carotid artery (ECA) was exposed and its branches coagulated.
  • perfusion fluid 125 mM NaCl, 2.5 mM KC1, 1.18 mM MgCl 2 and 1.26 mM CaCl ?
  • a 3-0 monofilament nylon suture was introduced into the internal carotid artery via an arteriotomy in the ECA and advanced until it lodged in the proximal region of the anterior cerebral artery, thus occluding the origin of the MCA.
  • the endovascular suture was retracted to allow reperfusion 2 hours after occlusion.
  • Body temperature was maintained normothermic throughout stroke surgery and reperfusion procedures.
  • the rats were dosed IP with 100 mg/kg 2- (phosphonomethyl) pentanedioic acid at -20 minute pre- occlusion and IV with 20 mg/kg/hr for 4 hours at the time of occlusion.
  • Dialysis samples were collected every 20 minutes from unanesthetized rats. Following 24 hours of reperfusion, the rats were sacrificed, their brains were removed, and 7 coronal sections (2 mm thick) were taken from the region beginning 1 mm from the frontal pole and ending just rostral to the cortico-cerebellar junction. Analysis of ischemic cerebral damage was achieved using TTC staining and computer assisted image analysis as described by Britton et al . (1997), supra .
  • both light and transmission electron microscopy (TEM) examination of the nerve 3 mm distal to the site of cryolesion demonstrated a significant increase in the number of myelinated axons (1.5-fold increase) and myelin thickness (20% increase, p ⁇ 0.005) , as compared to nerves in mice treated with vehicle.
  • FIG. 10(a) and FIG. 10(b) show a photomicrograph of this effect. Sections were stained with toluidme blue which stains myelin.
  • Sciatic nerves treated with 2- (phosphonomethyl) -pentanedioic acid containing implants compared with sciatic nerves treated with vehicle containing implants, exhibited an increase in myelinated axon number as well as an increase m myelin thickness.
  • 2 -( Phosphonomethyl ) pentanedioic acid was incorporated into silicone strips according to the method of Connold et al . , Developmental Bram Res , Vol. 28, pp. 99-104 (1986) , and was implanted at the site of cryolesion on day 0 and replaced on days 3, 6, 9 and 12. Approximately 2.5 ⁇ g/day of 2 - (phosphonomethyl) - pentanedioic acid was released from the silicone implants each day. Both right and left sciatic nerves of each mouse were lesioned; right-side nerves were treated with silicone implant strips containing vehicle alone while left-side nerves were treated with silicone implants containing 2- (phosphonomethyl) pentanedioic acid.
  • mice Fifteen days after surgery, the mice were sacrificed and their sciatic nerve segments were collected and processed for light microscopy and TEM analysis. Randomly chosen fields 2-3 mm distal to the lesion were qualitatively analyzed by light microscopy using 1 -micrometer-thick toluid e blue stained cross sections and photographic images were captured.
  • mice treated with MPTP and vehicle exhibited a substantial loss of functional dopaminergic terminals as compared to non-lesioned mice (approximately 68% loss) .
  • Lesioned mice receiving 2- (phosphonomethyl) pentanedioic acid (10 mg/kg) showed a significant recovery of TH- stained dopaminergic neurons (p ⁇ 0.001) .
  • 2- (phosphonomethyl) pentanedioic acid protects against MPTP-toxicity in mice.
  • MPTP lesioning of dopaminergic neurons in mice was used as an animal model of Parkinson's Disease, as described by Steiner, Proc . Na tl . Acad. Sci . , Vol. 94, pp. 2019-2024 (March 1997) .
  • four week old male CD1 white mice were dosed IP with 30 mg/kg of MPTP for 5 days.
  • 2- (Phosphonomethyl) pentanedioic acid (10 mg/kg) or a vehicle was administered SC along with the MPTP for 5 days, as well as for an additional 5 days following cessation of MPTP treatment.
  • the mice were sacrificed and their brains were removed and sectioned. Immunostainmg was performed on saggital and coronal bram sections using anti-tyrosine hydroxylase (TH) antibodies to quantitate survival and recovery of dopaminergic neurons.
  • TH anti-tyrosine hydroxylase
  • the rats were characterized as ambulatory or not on the basis of their assigned neurological scores (0 to 4) .
  • 73% of the 15 rats co-treated with 2- (phosphonomethyl) pentanedioic acid were ambulatory, in contrast to 14% of the 14 vehicle co-treated rats (p ⁇ 0.05).
  • Dynorphin- induced spinal cord injury was performed according to Long et al . , JPET, Vol. 269, No. 1, pp. 358- 366 (1993).
  • spinal subarachnoid injections were delivered using 30 -gauge needles inserted between the L4-L5 vertebrae of male Sprague-Dawley rats (300-350 g) .
  • the rats were anesthetized with halothane and dorsal midline incisions were made immediately rostral to the pelvic girdle.
  • the needle was advanced to pass into the subarachnoid space surrounding the cauda equina .
  • ALS Lateral Sclerosis
  • ALS Amyotrophic Lateral Sclerosis
  • ChAT activity for each treatment of the spinal cord organotypic cultures is provided below in TABLE XI and graphically presented in FIG. 13.
  • lumbar spinal cords were removed and sliced into 300 ⁇ M-thick-dorsal -ventral sections, and five slices were placed on Millipore CM semipermeable 30-mm-diameter membrane inserts. The inserts were placed on 1 ml of culture medium in 35-mm- diameter culture wells.
  • Culture medium consisted of 50% minimal essential medium and phosphate- free HEPES (25 mM) , 25% heat -inactivated horse serum, and 25% Hanks' balanced salt solution (GIBCO) supplemented with D- glucose (25.6 mg/ml) and glutamme (2 mM) , at a final pH of 7.2. Antibiotic and antifungal agents were not used. Cultures were incubated at 37° C in 5% C0 2 containing humidified environment (Forma Scientific) . Culture medium, along with any added pharmacological agents, was changed twice weekly. Chronic Toxicity Model with THA
  • ChAT activity was measured radiometrically by described methods using [ 3 H] acetyl-CoA (Amersham; Fonnum, 1975). Protein content of tissue homogenate was determined by a Coomassi Protein Assay kit (Pierce, Rockford, IL) .
  • Male Long-Evans rats were trained to self -administer nicotine on a fixed ratio schedule of reinforcement, as described by Corrigall et al . , Psychopharmacology , Vol. 104, No. 2, pp. 171-176 (1991) and Corrigall et al . , Psychopharmacology, Vol. 107, Nos. 2-3, pp. 285-289 (1992).
  • male Long-Evans rats were food deprived for a short period of time (24-48 hours) and trained to press a lever in an operant responding chamber on an FR-1 schedule of food reinforcement. Once trained, each rat was surgically prepared with a chronic intravenous catheter implanted into the jugular vein. The rats were allowed 1 week to recover from surgery.
  • Nicotine self-administration sessions were 60 minutes in duration. Each nicotine infusion contained 30 ⁇ g of nicotine/kg rat and were delivered in a volume of 54 ⁇ l over an infusion duration of 0.3 seconds. 15 minutes before the self- administration sessions, the rats were pre-treated intraperitoneally with 2- (phosphonomethyl) -pentanedioic acid at doses of 10, 20 and 30 mg/kg. Food intake was monitored during the nicotine self-administration sessions to assess non-specific drug effects.
  • Methyl -O-benzylphosphinic acid (3.53 g, 20.7 mmol) in 200 L of dichloromethane was cooled to -5° C under an atmosphere of nitrogen. T ⁇ ethylamme (3.2 g, 32 mmol) was added via syringe followed by trimethylsilyl chloride (2.9 g, 27 mmol) . The reaction mixture was stirred and warmed to room temperature over 1 hour. Dibenzyl 2- methylenepentanedioate (2, 6.0 g, 18.5 mmol) in 10 mL of dichloromethane was added. The mixture was then stirred at room temperature overnight.
  • the reaction mixture was cooled to 0° C and trimethylalummum (9 mL, 18 mmol, 2.0 M in dichloromethane) was added. The flask was warmed and stirred for 72 hours. The clear light yellow solution was cooled to 5° C and quenched by the slow addition of 5% hydrochloric acid. The quenched reaction mixture was warmed to room temperature and the organic layer removed. The organic layer was washed with 5% hydrochloric acid and with water. The organics were dried (MgS0 4 ) and evaporated under reduced pressure to give 8 g of a clear light yellow oil.
  • Butylphosphmic acid (2.0 g, 16 mmol) in 80 mL of dry dichloromethane was cooled to 0° C under an atmosphere of nitrogen. Tnethylamine (6.7 g, 66 mmol) was added followed by t ⁇ methylsilyl chloride (58 mL, 58 mmol, 1.0 M in dichloromethane) . The mixture was stirred at 0° C for 10 minutes and dibenzyl 2- methylenepentanedioate (2) (6.4 g, 20 mmol) m 20 mL of dichloromethane was added. The cold bath was removed and the reaction warmed to room temperature and stirred overnight.
  • the mixture was then cooled to 0° C and quenched by the slow addition of 5% hydrochloric acid (50 mL) .
  • the dichloromethane layer was then removed and washed with 5% hydrochloric acid and with brine.
  • the organic layer was dried (MgS0 4 ) and evaporated to give a clear light golden liquid.
  • the liquid was purified by flash chromatography and eluted with 3:1 hexane/ethyl acetate containing 5% acetic acid.
  • Benzylphosphmic acid (2.3 g, 15 mmol) 150 mL of dry dichloromethane was cooled to 0° C under a nitrogen atmosphere. T ⁇ ethylamme (6.5 g, 65 mmol) was added followed by trimethylsilyl chloride (5.8 g, 54 mmol) while the reaction temperature was maintained at 0° C.
  • Phenethylphosphmic acid 1.0 g, 5.9 mmol m 50 mL of dry dichloromethane was cooled to -5° C under a nitrogen atmosphere. Triethylamme (2.3 g, 23 mmol) was added followed by tnmethylsilyl chloride (2.2 g, 21 mmol) while the reaction temperature was maintained at 0° C. After 10 minutes dibenzyl 2 -methylenepentanedioate (2) (1.7 g, 5.2 mmol) in 10 mL of dichloromethane was added over 10 minutes. The reaction mixture was left to warm to room temperature and stirred overnight. The clear solution was cooled to 0° C and quenched with 5% hydrochloric acid followed by removal of the organic layer. The organic layer was washed with brine, dried
  • Benzyl acrylate 500 g, 3.0 mol was heated in an oil bath to 100° C. Heating was stopped and HMPT (10 g, 61 mmol) was added dropwise while maintaining an internal temperature below 140° C. Once addition was complete, the mixture was stirred and cooled to room temperature. A slurry of silica (5:1 Hexane/EtOAc) was added and the mixture was placed in a column containing a plug of dry silica. The column was washed with 1:1 Hexane/EtOAc and the fractions were combined and evaporated to give 450 g of clear light golden liquid. The liquid was distilled under high vacuum (200 ⁇ Hg) at 185° C to give 212 g (42%) of a clear and colorless liquid.
  • EXAMPLE 15 A patient is at risk of injury from an ischemic event.
  • the patient may be pretreated with an effective amount of a NAALADase inhibitor or a pharmaceutical composition of the present invention. It is expected that after the pretreatment, the patient would be protected from any injury due to the ischemic event.
  • EXAMPLE 16 A patient is suffering from an ischemic event.
  • the patient may be administered during or after the event, an effective amount of a NAALADase inhibitor or a pharmaceutical composition of the present invention. It is expected that after the treatment, the patient would recover or would not suffer any significant injury due to the ischemic event .
  • a patient has suffered injury from an ischemic event.
  • the patient may be administered an effective amount of a NAALADase inhibitor or a pharmaceutical composition of the present invention. It is expected that after the treatment, the patient would recover from the injury due to the ischemic event.
  • a patient is suffering from a glutamate abnormality.
  • the patient may then be administered an effective amount of a NAALADase inhibitor or a pharmaceutical composition of the present invention. It is expected that after the treatment, the patient would be protected from further injury due to the glutamate abnormality or would recover from the glutamate abnormality.
  • EXAMPLE 19 A patient is suffering from or has suffered from a nervous insult, such as that arising from a neurodegenerative disease or a neurodegenerative process. The patient may then be administered an effective amount of a NAALADase inhibitor or a pharmaceutical composition of the present invention. It is expected that after the treatment, the patient would be protected from further injury due to the nervous insult or would recover from the nervous insult.
  • a patient is suffering from Parkinson's disease.
  • the patient may then be administered an effective amount of a NAALADase inhibitor or a pharmaceutical composition of the present invention. It is expected that after the treatment, the patient would be protected from further neurodegeneration or would recover from Parkinson's disease .
  • EXAMPLE 21
  • a patient is suffering from ALS.
  • the patient may then be administered an effective amount of a NAALADase inhibitor or a pharmaceutical composition of the present invention. It is expected that after the treatment, the patient would be protected from further neurodegeneration or would recover from ALS.
  • EXAMPLE 22 A patient is suffering from epilepsy. The patient may then be administered an effective amount of a NAALADase inhibitor or a pharmaceutical composition of the present invention. It is expected that after the treatment, the patient would be protected from further neurodegeneration or would recover from epilepsy.
  • a patient is suffering from abnormalities m myel ation/demyelmation processes
  • the patient may then be administered an effective amount of a NAALADase inhibitor or a pharmaceutical composition of the present invention. It is expected that after the treatment, the patient would be protected from further neurodegeneration or would recover from the abnormalities m myelmation/demyelmation processes.
  • a patient is suffering from or has suffered from a cerebrovascular accident, such as stroke.
  • the patient may then be administered an effective amount of a NAALADase inhibitor or a pharmaceutical composition of the present invention. It is expected that after the treatment, the patient would be protected from or would recover from any injury due to the cerebrovascular accident .
  • EXAMPLE 25 A patient is suffering from a head trauma. The patient may then be administered an effective amount of a NAALADase inhibitor or a pharmaceutical composition of the present invention. It is expected that after the treatment, the patient would be protected from or would recover from any ischemic bra , spinal or peripheral injury resulting from the head trauma.
  • a patient is suffering from a spinal trauma.
  • the patient may then be administered an effective amount of a NAALADase inhibitor or a pharmaceutical composition of the present invention. It is expected that after the treatment, the patient would be protected from or would recover from any ischemic injury resulting from the
  • a patient is about to undergo surgery.
  • the patient may be administered an effective amount of a NAALADase inhibitor or a pharmaceutical composition of the present invention. It is expected that after the treatment, the patient would not develop any ischemic bram, spmal or peripheral injury resulting from or associated with the surgery.
  • a patient is suffering from focal ischemia, such as that associated with thromboembolytic occlusion of a cerebral vessel, traumatic head injury, edema or bram tumors.
  • the patient may then be administered an effective amount of a NAALADase inhibitor or a pharmaceutical composition of the present invention. It is expected that after the treatment, the patient would be protected from or would recover from any bram, spmal or peripheral injury resulting from the focal ischemia.
  • a patient is suffering from global ischemia.
  • the patient may then be administered an effective amount of a NAALADase inhibitor or a pharmaceutical composition of
  • SUBSTTTUTESHEET(RULE26) the present invention. It is expected that after the treatment, the patient would be protected from or would recover from any bram, spmal or peripheral injury resulting from the global ischemia.
  • EXAMPLE 30 A patient is suffering from a cardiac arrest. The patient may then be administered an effective amount of a NAALADase inhibitor or a pharmaceutical composition of the present invention It is expected that after the treatment, the patient would be protected from or would recover from any ischemic bram, spmal or peripheral injury associated with the cardiac arrest.
  • a patient is suffering from hypoxia, asphyxia or perinatal asphyxia.
  • the patient may then be administered an effective amount of a NAALADase inhibitor or a pharmaceutical composition of the present invention. It is expected that after the treatment, the patient would be protected from or would recover from any ischemic bra , spmal or peripheral injury associated with the hypoxia, asphyxia or perinatal asphyxia.
  • a patient is suffering from a cerebro-cortical injury.
  • the patient may then be administered an effective amount of a NAALADase inhibitor or a pharmaceutical composition of the present invention. It is expected that after the treatment, the patient would be protected from or would recover from any ischemic brain injury resulting from the cerebro-cortical injury.
  • the patient is suffering from an injury to the caudate nucleus.
  • the patient may then be administered an effective amount of a NAALADase inhibitor or a pharmaceutical composition of the present invention. It is expected that after the treatment, the patient would be protected from or would recover from any ischemic brain injury resulting from the injury to the caudate nucleus .
  • a patient is suffering from a cortical injury due to a condition identified in these examples.
  • the patient may then be administered an effective amount of a NAALADase inhibitor or a pharmaceutical composition of the present invention. It is expected that after the treatment, the patient would be protected from further injury, or would exhibit at least 65% to at least 80% recovery from the cortical injury.
  • EXAMPLE 35
  • a patient is suffering from multiple sclerosis.
  • the patient may then be administered an effective amount of a NAALADase inhibitor or a pharmaceutical composition of the present invention. It is expected that after the treatment, the patient would be protected from further demyelmation or would recover from multiple sclerosis.
  • EXAMPLE 36 A patient is suffering from a peripheral neuropathy caused by Guillam-Barre syndrome. The patient may then be administered an effective amount of a NAALADase inhibitor or a pharmaceutical composition of the present invention. It is expected that after the treatment, the patient would be protected from further demyelmation or would recover from the peripheral neuropathy.
  • the patient is suffering from alcoholism.
  • the patient may then be administered an effective amount of a NAALADase inhibitor or a pharmaceutical composition of the present invention. It is expected that after the treatment, the patient's craving for alcohol would be suppressed.
  • a patient is suffering from nicotine dependence.
  • the patient may then be administered an effective amount of a NAALADase inhibitor or a pharmaceutical composition of the present invention. It is expected that after the treatment, the patient's craving for nicotine would be suppressed.
  • EXAMPLE 39 The patient is suffering from cocaine dependence. The patient may then be administered an effective amount of a NAALADase inhibitor or a pharmaceutical composition of the present invention. It is expected that after the treatment, the patient's craving for cocaine would be suppressed.
  • a patient is suffering from heroine dependence.
  • the patient may then be administered an effective amount of a NAALADase inhibitor or a pharmaceutical composition of the present invention. It is expected that after the treatment, the patient's craving for heroine would be suppressed.
  • the patient is suffering from compulsive overeating,
  • SUBSTTTUTE SHEET (RULE 26) obesity or severe obesity.
  • the patient may then be administered an effective amount of a NAALADase inhibitor or a pharmaceutical composition of the present invention. It is expected that after the treatment, the patient's compulsion to eat would be suppressed.
  • a patient is suffering from pathological gambling.
  • the patient may then be administered an effective amount of a NAALADase inhibitor or a pharmaceutical composition of the present invention. It is expected that after the treatment, the patient's compulsion to gamble would be suppressed.
  • the patient is suffering from ADD.
  • the patient may then be administered an effective amount of a NAALADase inhibitor or a pharmaceutical composition of the present invention. It is expected that after the treatment, the patient's symptoms of inattention, impulsivity and/or hyperactivity would be suppressed.
  • a patient is suffering from Tourette's syndrome.
  • the patient may then be administered an effective amount of a NAALADase inhibitor or a pharmaceutical composition of the present invention. It is expected that after the treatment, the patient ' s simple , complex, respiratory and vocal tics would be suppressed.
  • a patient is diagnosed with a disease, disorder or condition as identified in these examples.
  • An effective amount of a NAALADase inhibitor or a pharmaceutical composition of the present invention may then be administered to the patient intravenously, intramuscularly, intraventricularly to the brain, rectally, subcutaneously , intranasally, through a catheter with or without a pump, orally, through a transdermal patch, topically, or through a polymer implant. After the treatment, the patient's condition would be expected to improve.
  • a patient is diagnosed with a disease, disorder or condition as identified in these examples.
  • a NAALADase inhibitor or a pharmaceutical composition of the present invention may then be administered to the patient in the form of a 100 mg/kg bolus, optionally followed by a 20 9/kg P er hour intravenous infusion over a two-hour period. After the treatment, the patient's condition would be expected to improve.

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Abstract

L'invention porte sur une composition pharmaceutique et sur une méthode de traitement de troubles d'ordre compulsionnel à l'aide d'un inhibiteur de la NAALADase.
PCT/US1997/014417 1996-09-27 1997-08-15 Compositions pharmaceutiques et methodes de traitement de troubles d'ordre compulsionnel a l'aide d'un inhibiteur de la naaladase WO1998013044A1 (fr)

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EP97939427A EP0949922A1 (fr) 1996-09-27 1997-08-15 Compositions pharmaceutiques et methodes de traitement de troubles d'ordre compulsionnel a l'aide d'un inhibiteur de la naaladase
AU41518/97A AU4151897A (en) 1996-09-27 1997-08-15 Pharmaceutical compositions and methods of treating compulsive disorders using naaladase inhibitors
CA002264158A CA2264158A1 (fr) 1996-09-27 1997-08-15 Compositions pharmaceutiques et methodes de traitement de troubles d'ordre compulsionnel a l'aide d'un inhibiteur de la naaladase
JP51563698A JP2002514185A (ja) 1996-09-27 1997-08-15 ＮＡＡＬＡＤａｓｅ阻害剤を用いる強迫性障害の治療の医薬組成物及び方法

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US08/718,703 US5824662A (en) 1996-09-27 1996-09-27 Treatment of global and focal ischemia using naaladase inhibitors
US08/718,703 1996-09-27
US08/778,733 1996-12-31
US08/778,733 US5863536A (en) 1996-12-31 1996-12-31 Phosphoramidate derivatives
US08/775,586 1996-12-31
US08/775,586 US5795877A (en) 1996-12-31 1996-12-31 Inhibitors of NAALADase enzyme activity
US08/825,997 US5962521A (en) 1997-04-04 1997-04-04 Hydroxamic acid derivatives
US08/835,572 1997-04-09
US08/835,572 US5902817A (en) 1997-04-09 1997-04-09 Certain sulfoxide and sulfone derivatives
US08/842,360 1997-04-24
US08/842,360 US6054444A (en) 1997-04-24 1997-04-24 Phosphonic acid derivatives
US08/858,985 US6025344A (en) 1996-06-17 1997-05-27 Certain dioic acid derivatives useful as NAALADase inhibitors
US08/858,985 1997-05-27
US08/863,624 1997-05-27
US08/863,624 US6046180A (en) 1996-06-17 1997-05-27 NAALADase inhibitors
US08/884,479 US6017903A (en) 1996-09-27 1997-06-27 Pharmaceutical compositions and methods of treating a glutamate abnormality and effecting a neuronal activity in an animal using NAALADase inhibitors
US08/884,479 1997-06-27
US08/825,997 1997-06-27

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WO1998045256A1 (fr) * 1997-04-04 1998-10-15 Guilford Pharmaceuticals Inc. Derives d'acide hydroxamique
WO1998047906A1 (fr) * 1997-04-24 1998-10-29 Guilford Pharmaceuticals Inc. Derives d'acide phosphonique
WO1999033847A1 (fr) * 1997-12-31 1999-07-08 Guilford Pharmaceuticals Inc. Derives d'acide alcanoique phosphinique
US5977090A (en) * 1996-09-27 1999-11-02 Guilford Pharmaceuticals Inc. Pharmaceutical compositions and methods of treating compulsive disorders using NAALADase inhibitors
WO2000001668A2 (fr) * 1998-07-06 2000-01-13 Guilford Pharmaceuticals Inc. INHIBITEURS DE NAALADase UTILES COMME COMPOSES ET COMPOSITIONS PHARMACEUTIQUES
EP0994707A1 (fr) * 1997-05-27 2000-04-26 Guilford Pharmaceuticals Inc. Inhibiteurs de l'activite enzymatique de naaladase
WO2001001974A2 (fr) * 1999-07-01 2001-01-11 Guilford Pharmaceuticals Inc. Compositions pharmaceutiques et procedes permettant de traiter l'anxiete, les troubles anxieux et la perte de memoire, par utilisation d'inhibiteurs de naaladase
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US5977090A (en) * 1996-09-27 1999-11-02 Guilford Pharmaceuticals Inc. Pharmaceutical compositions and methods of treating compulsive disorders using NAALADase inhibitors
WO1998045256A1 (fr) * 1997-04-04 1998-10-15 Guilford Pharmaceuticals Inc. Derives d'acide hydroxamique
US5962521A (en) * 1997-04-04 1999-10-05 Guilford Pharmaceuticals Inc. Hydroxamic acid derivatives
US6054444A (en) * 1997-04-24 2000-04-25 Guilford Pharmaceuticals Inc. Phosphonic acid derivatives
WO1998047906A1 (fr) * 1997-04-24 1998-10-29 Guilford Pharmaceuticals Inc. Derives d'acide phosphonique
US6288046B1 (en) 1997-04-24 2001-09-11 Guilford Pharmaceuticals Inc. Phosphonic acid derivatives
EP0994707A4 (fr) * 1997-05-27 2001-11-14 Guilford Pharm Inc Inhibiteurs de l'activite enzymatique de naaladase
EP0994707A1 (fr) * 1997-05-27 2000-04-26 Guilford Pharmaceuticals Inc. Inhibiteurs de l'activite enzymatique de naaladase
WO1999033847A1 (fr) * 1997-12-31 1999-07-08 Guilford Pharmaceuticals Inc. Derives d'acide alcanoique phosphinique
WO2000001668A3 (fr) * 1998-07-06 2000-09-21 Guilford Pharm Inc INHIBITEURS DE NAALADase UTILES COMME COMPOSES ET COMPOSITIONS PHARMACEUTIQUES
WO2000001668A2 (fr) * 1998-07-06 2000-01-13 Guilford Pharmaceuticals Inc. INHIBITEURS DE NAALADase UTILES COMME COMPOSES ET COMPOSITIONS PHARMACEUTIQUES
JP2010001312A (ja) * 1998-07-06 2010-01-07 Eisai Corp Of North America 医薬化合物及び組成物として有用なＮＡＡＬＡＤａｓｅ阻害剤
US6458775B1 (en) 1998-07-06 2002-10-01 Guilford Pharmaceutical Inc. NAALADase inhibitors useful as pharmaceutical compounds and compositions
WO2001001974A2 (fr) * 1999-07-01 2001-01-11 Guilford Pharmaceuticals Inc. Compositions pharmaceutiques et procedes permettant de traiter l'anxiete, les troubles anxieux et la perte de memoire, par utilisation d'inhibiteurs de naaladase
WO2001001974A3 (fr) * 1999-07-01 2002-03-07 Guilford Pharm Inc Compositions pharmaceutiques et procedes permettant de traiter l'anxiete, les troubles anxieux et la perte de memoire, par utilisation d'inhibiteurs de naaladase
EP1212055A4 (fr) * 1999-08-16 2005-09-07 Revaax Pharmaceuticals Llc Composition neurotherapeutique et procede associe
US7842683B2 (en) 1999-08-16 2010-11-30 Revaax Pharmaceuticals, Llc Neurotherapeutic compositions and method
EP1212055A1 (fr) * 1999-08-16 2002-06-12 Revaax Pharmaceuticals LLC Composition neurotherapeutique et procede associe
WO2001014390A3 (fr) * 1999-08-20 2001-09-27 Guilford Pharmaceuticals DERIVES DE LIGAND DES RECEPTEURS DU GLUTAMATE METABOTROPIQUE UTILISES COMME INHIBITEURS DE L'ENZYME NAALADase
US6313159B1 (en) 1999-08-20 2001-11-06 Guilford Pharmaceuticals Inc. Metabotropic glutamate receptor ligand derivatives as naaladase inhibitors
WO2001014390A2 (fr) * 1999-08-20 2001-03-01 Guilford Pharmaceuticals DERIVES DE LIGAND DES RECEPTEURS DU GLUTAMATE METABOTROPIQUE UTILISES COMME INHIBITEURS DE L'ENZYME NAALADase
WO2003080631A3 (fr) * 2002-03-21 2004-04-15 Schering Ag Inhibiteurs de plasma carboxypeptidase b
US7528173B2 (en) 2002-03-21 2009-05-05 Schering Aktiengesellshaft Plasma carboxypeptidase B inhibitors
EP2204373A1 (fr) * 2002-03-21 2010-07-07 Bayer Schering Pharma Aktiengesellschaft Dérivés de l'acid phosphonic comme inhibiteurs de Plasma Carboxypeptidase B
US8008325B2 (en) 2002-03-21 2011-08-30 Bayer Schering Pharma Ag Plasma carboxypeptidase B inhibitors
WO2004078180A2 (fr) * 2003-03-03 2004-09-16 Guilford Pharmaceuticals Inc. Inhibiteurs de naaladase pour le traitement de la tolerance aux opiaces
WO2004078180A3 (fr) * 2003-03-03 2005-05-06 Guilford Pharm Inc Inhibiteurs de naaladase pour le traitement de la tolerance aux opiaces
US7973069B2 (en) 2004-07-14 2011-07-05 Ptc Therapeutics, Inc. Methods for treating hepatitis C
WO2011073286A1 (fr) 2009-12-18 2011-06-23 Bayer Schering Pharma Aktiengesellschaft Inhibiteurs d'antigènes membranaires spécifiques de la prostate
EP2338892A1 (fr) 2009-12-18 2011-06-29 Bayer Schering Pharma Aktiengesellschaft Inhibiteurs d'antigène de membrane spécifique à la prostate

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AU4151897A (en) 1998-04-17
ID18382A (id) 1998-04-02
CA2264158A1 (fr) 1998-04-02
JP2002514185A (ja) 2002-05-14
EP0949922A1 (fr) 1999-10-20

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