Metabotropic glutamate receptor ligand derivatives as naaladase inhibitors

The present invention relates to metabotropic glutamate receptor ligand derivatives and methods of using the same to inhibit NAALADase enzyme activity, to effect neuronal activities, to inhibit angiogenesis, and to treat glutamate abnormalities, compulsive disorders, pain, diabetic neuropathy, and prostate diseases, as well as pharmaceutical compositions comprising the same.

BACKGROUND OF THE INVENTION
 The present invention relates to metabotropic glutamate receptor ligand
 derivatives, pharmaceutical compositions comprising such derivatives and
 methods of their use to inhibit NAALADase enzyme activity, thereby
 effecting neuronal activities, inhibiting angiogenesis and treating
 glutamate abnormalities, compulsive disorders, pain, diabetic neuropathy,
 and prostate diseases. When a metabotropic glutamate receptor ligand,
 preferably an mGluR3 receptor ligand, is attached to a metal chelating
 group capable of interacting with the metal atom(s) at the active site of
 NAALADase, it is expected that the resulting compound will be a potent and
 specific NAALADase inhibitor.
 The NAALADase enzyme, also known as prostate specific membrane antigen (PSM
 or PSMA) and human glutamate carboxypeptidase II (GCP II), catalyzes the
 hydrolysis of the neuropeptide N-acetyl-aspartyl-glutamate ("NAAG") to
 N-acetyl-aspartate ("NAA") and glutamate. Based upon amino acid sequence
 homology, NAALADase has been assigned to the M28 family of peptidases.
 There is, as yet, no crystallographic evidence of the structure of the
 NAALADase enzyme.
 Recent studies have implicated NAALADase in the pathogenesis of
 glutamate-mediated disorders. Neuropathological studies on post-mortem
 tissue from patients with amyotrophic lateral sclerosis (ALS) indicate
 large decreases of N-acetylaspartate (NAA) and N-acetylaspartylglutamate
 (NAAG) tissue concentrations occurring in association with neuronal
 degeneration, and increases of NAA and NAAG in cerebral spinal fluid (CSF)
 from patients with ALS. Concordantly, abnormal NAAG levels and NAALADase
 activity have also been observed in post-mortem prefrontal and limbic
 brain tissue of schizophrenic patients. Autopsy studies also suggest a
 strong correlation between NAAG/NAA and Alzheimer's disease. In
 post-mortem brain tissue, NAA and NAAG levels were found to be selectively
 decreased in brain areas (hippo campus and amygdala) affected by
 Alzheimer's disease pathology.
 Glutamate serves as the predominant excitatory neurotransmitter in the
 central nervous system (CNS). Neurons release glutamate in greater
 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 in 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.sup.2+ and
 Na.sup.+ into the cells and K.sup.+ out of the cells. These flows of ions,
 especially the influx of Ca.sup.2+, cause over-stimulation of the neurons.
 The over-stimulated neurons secrete more glutamate, creating a feedback
 amplification effect which is believed to ultimately result in cell death
 via the production of proteases, lipases, and free radicals.
 Excessive activation of glutamate receptors has been implicated in various
 neurological diseases and conditions, including spinal cord injury,
 epilepsy, stroke, Alzheimer's disease, Parkinson's Disease, Amyotrophic
 Lateral Sclerosis (ALS), Huntington's Disease, schizophrenia, acute and
 chronic pain, ischemia and neuronal loss following hypoxia, hypoglycemia,
 ischemia, trauma, nervous insult, compulsive disorders (particularly drug
 and alcohol dependence), demyelinating diseases, peripheral neuropathies,
 and diabetic neuropathy.
 In particular, glutamatergic abnormalities have been associated with
 schizophrenia. For example, phencyclidine (PCP) and other antagonists of
 N-methyl-D-aspartate (NMDA) receptors induce psychotomimetic properties in
 healthy individuals and exacerbate preexisting symptoms of schizophrenia,
 suggesting that a depression of glutamate transmission might contribute to
 schizophrenia. Additionally, it has been reported that antagonists of
 non-NMDA receptors or pretreatments that attenuate glutamate release
 reduce mnemonic and other behavioral effects of NMDA receptor antagonists.
 Studies have also shown that stimulation of certain subtypes of mGlu
 receptors mediates presynaptic depression and decreases evoke release of
 glutamate.
 Recent studies have also advanced a glutamatergic basis for compulsive
 disorders, particularly drug dependence. For example, 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.
 Post mortem examinations of histologically normal brains from alcoholics
 have shown that chronic alcoholism moderately increases the density of the
 NMDA subtype of glutamate receptors in the frontal cortex. This
 up-regulation may represent a stage of ethanol-induced chronic
 neurotoxicity. As such, neurobiological effects of alcoholism, including
 intoxication, withdrawal seizures, delirium tremens, Wernicke-Korsakoff
 syndrome and fetal alcohol syndrome, can be understood as a spectrum of
 the consequences of ethanol's effect on the glutamatergic system. In this
 regard, alcoholism may be considered another member of the expanding
 family of glutamate-related neurological disorders.
 The glutamatergic system has also been implicated in the behavioral effects
 of other abused drugs. For example, studies have shown that glutamatergic
 antagonists block motor-stimulating activities induced by amphetamine and
 cocaine, and glutamatergic agonists cause the same stereotype as that
 produced by amphetamine. These results represent pharmacological evidence
 that the expression of the stereotypic effect of psychomotor stimulants
 involves the glutamatergic system.
 Epidemiologic studies have revealed a strong correlation between drug
 dependence and other compulsive disorders. Additionally, a common genetic
 anomaly has been found among people with alcoholism, cocaine dependence,
 nicotine dependence, pathological gambling, attention deficit disorder
 (ADD), Tourette's syndrome, compulsive overeating and obesity. Such
 disorders are believed to be manifestations of the effects of
 excitotoxicity.
 Based on the above findings, the present inventors tested and found
 NAALADase inhibitors to be efficacious in the pharmacotherapy of glutamate
 abnormalities, such as drug dependence, diabetic neuropathy, pain,
 schizophrenia, ischemic injury, and anxiety.
 Ischemic injury may occur as a focal or global disruption of blood supply.
 Following ischemic insult, widespread neuronal depolarization occurs.
 Depolarization stimulates release of the stored neurotransmitter glutamate
 and results in impaired capacity of glutamate uptake mechanisms. Impaired
 glutamate uptake and enhanced glutamate release contribute to sustained
 elevation of extracellular glutamate in ischemic tissue, and may result in
 tissue damage. As more damage occurs, more glutamate may be released.
 Although not limited to any particular theory, it is believed that by
 interfering with or eliminating this cascade of glutamate toxicity, the
 compositions and methods of the present convention may be clinically
 useful in curbing the progression of ischemic injury.
 Afferent pain fibers of the A-.delta. and C types have their primary cell
 bodies in the dorsal root ganglia; central extensions of these nerve cells
 project, via the dorsal root, to the dorsal horn of the spinal cord or to
 the nucleus of the trigeminal nerve; the peripheral terminations of these
 primary pain receptors are the branch nerve endings in the skin and other
 organs. Excitatory amino acids, including glutamate, and ATP are putative
 neurotransmitters at the dorsal horn terminus of primary A-.delta. fibers.
 The conscious awareness or perception of pain occurs only when the pain
 impulses actually reach the thalamocortical level. Although not limited to
 any particular theory, it is believed that by interfering with such nerve
 impulses, the compositions and methods of the present convention may be
 clinically useful in limiting or eliminating pain.
 Diabetic neuropathy is a slowly progressive, mixed sensorimotor and
 autonomic neuropathy. A variety of pathogenic mechanisms have been
 proposed for diabetic neuropathy, including alteration in nerve metabolism
 induced by ischemia and, in some cases, autoimmunity. Although not limited
 to any particular theory, it is believed that by interfering with or
 eliminating these effects, the compositions and methods of the present
 convention may be clinically useful in curbing the progression of diabetic
 neuropathy.
 Excessive activation of glutamate receptors has been implicated in anxiety
 and anxiety disorders. Significantly higher glutamate plasma levels have
 been detected in patients with mood disorders than in comparison subjects.
 Studies also suggest that the pharmacological effect of anxiolytic agents
 is mediated through the glutamatergic system. Although not limited to any
 particular theory, it is believed that by interfering with or eliminating
 these effects, the compositions and methods of the present convention may
 be clinically useful in curbing anxiolytic activity.
 Most research and development activity to date have focused on blocking
 post-synaptic glutamate receptors with compounds such as NMDA antagonists,
 glycine antagonists, and other post-synaptic excitatory amino acid (EAA)
 receptor blockers. Unfortunately, these efforts have proven difficult
 because each receptor has multiple sites to which glutamate may bind; in
 addition, these agents produce severe toxicities even under normal
 conditions, thus limiting their clinical use. Although not limited to any
 one particular theory, it is believed that NAALADase inhibitors block
 glutamate release pre-synaptically without interacting with post-synaptic
 glutamate receptors. Since NAALADase inhibitors do not appear to alter
 basal glutamate levels, they may be devoid of the behavioral toxicities
 associated with post-synaptic glutamate antagonists.
 In addition to glutamate, NAALADase has also been associated with
 prostate-specific membrane antigen (PSMA). In particular, it has been
 shown that PSMA cDNA confers NAALADase activity and that NAALADase and
 PSMA exhibit at least 86% homologous sequence identity. Carter et al.,
 Proc. Natl. Acad. Sci., Vol. 93, pp. 749-753 (1996). The molecular cloning
 of PSMA has been reported as a potential prostate carcinoma marker and
 hypothesized to serve as a target for imaging and cytotoxic treatment
 modalities for prostate cancer. Additionally, PSMA antibodies,
 particularly indium-111 labelled and itrium labelled PSMA antibodies, have
 been described and examined clinically for the diagnosis and treatment of
 prostate cancer. PSMA is expressed in prostatic ductal epithelium and is
 present in seminal plasma, prostatic fluid and urine.
 Applicants have found NAALADase inhibitors to be effective in treating
 prostate diseases, particularly prostate cancer. Although not limited to
 any particular theory, it is believed that NAALADase inhibitors inhibit
 PSMA activity. Since mAbs to PSMA have been found to target 23
 non-prostate carcinomas (Lui et al., Science Research, Vol. 57, pp.
 3629-34 (1997)), the present inventors hypothesize that NAALADase
 inhibitors would also be effective in treating non-prostate cancers,
 particularly in tissues where NAALADase resides, such as the brain, kidney
 and testis.
 NAALADase has also been found in neovasculature (new blood vessels). The
 present inventors have discovered that NAALADase inhibitors inhibit or
 prevent growth of neovasculature (angiogenesis), thereby providing
 potential therapeutic applications in treating diseases dependent upon
 angiogenesis. Examples of angiogenesis-dependent diseases include without
 limitation rheumatoid arthritis, cardiovascular disease, neovascular
 diseases of the eye, peripheral vascular disorders, and dermatologic
 ulcers. Angiogenesis is also essential for normal physiological processes,
 such as growth, fertility and soft tissue wound healing.
 Cancer is another disease dependent upon angiogenesis. Cancer tumor cells
 secrete or release angiogenic substances that activate nearby endothelial
 cells. These endothelial cells respond by expressing a cell autonomous
 pattern of behavior that culminates in the formation of new blood vessels.
 Since research has demonstrated that angiogenesis is necessary to sustain
 the growth, invasion and metastasis of cancer tumors, the neovasculature
 inhibiting activity of NAALADase inhibitors further supports their utility
 in treating all types of cancers.
 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-phenanthroline, metal chelators such
 as EGTA and EDTA, and peptide analogs such as quisqualic acid and
 .beta.-NAAG. These compounds either have toxic side effects or are
 incapable of being administered in pharmaceutically effective amounts.
 NAAG is an agonist at group II metabotropic glutamate receptors,
 specifically mGluR3 receptors. When a metabotropic glutamate receptor
 ligand, preferably an mGluR3 receptor ligand, is attached to a metal
 chelating group capable of interacting with the metal atom(s) at the
 active site of NAALADase, it is expected that the resulting compound will
 be a potent and specific NAALADase inhibitor. In view of the broad range
 of potential applications, a need exists for new NAALADase inhibitors,
 pharmaceutical compositions comprising such inhibitors, and methods of
 their use.
 SUMMARY OF THE INVENTION
 The present invention relates to metabotropic glutamate receptor ligand
 compounds and compositions useful for inhibiting N-Acetylated
 .alpha.-Linked Acidic Dipeptidase (NAALADase) enzyme activity, thereby
 effecting neuronal activities, inhibiting angiogenesis and treating
 glutamate abnormalities, compulsive disorders, prostate diseases, pain and
 diabetic neuropathy.
 More specifically, the present invention relates to a compound of formula
 I:
 ##STR1##
 or a pharmaceutically acceptable equivalent, wherein:
 either J and K are taken together with one or more additional atoms
 independently selected from the group consisting of C, O, S, and N in
 chemically reasonable substitution patterns to form a 3-7 membered
 saturated or unsaturated heterocyclic or carbocyclic ring, and L is --CH,
 or J, K, and L are taken together with one or more additional atoms
 independently selected from the group consisting of C, O, S, and N in
 chemically reasonable substitution patterns to form a 4-8 membered
 saturated or unsaturated, mono-, bi-, or tricyclic, hetero- or carbocyclic
 ring structure;
 Z is a metal chelating group;
 R.sub.1 and R.sub.2 are independently hydrogen, C.sub.1 -C.sub.9 alkyl,
 C.sub.2 -C.sub.9 alkenyl, C3-C8 cycloalkyl, C.sub.5 -C.sub.7 cycloalkenyl,
 or Ar, wherein each said alkyl, alkenyl, cycloalkyl, cycloalkenyl, or Ar
 is independently unsubstituted or substituted with one or more
 substituent(s); and
 Ar is a carbocyclic or heterocyclic moiety which is unsubstituted or
 substituted with one or more substituent(s).
 In a preferred embodiment of formula I, R.sub.1 and R.sub.2 are each
 hydrogen.
 A preferred embodiment of the present invention relates to a compound of
 formula II:
 ##STR2##
 or a pharmaceutically acceptable equivalent, wherein:
 Z is a metal chelating group;
 R.sub.1 and R.sub.2 are independently hydrogen, C.sub.1 -C.sub.9 alkyl,
 C.sub.2 -C.sub.9 alkenyl, C.sub.3 -C.sub.8 cycloalkyl, C.sub.5 -C.sub.7
 cycloalkenyl, or Ar, wherein each said alkyl, alkenyl, cycloalkyl,
 cycloalkenyl, or Ar is independently unsubstituted or substituted with one
 or more substituent(s); and
 Ar is a carbocyclic or heterocyclic moiety which is unsubstituted or
 substituted with one or more substituent(s).
 In a preferred embodiment of formula II, R.sub.1 and R.sub.2 are each
 hydrogen.
 Another preferred embodiment of the present invention relates to a compound
 of formula III:
 ##STR3##
 or a pharmaceutically acceptable equivalent, wherein:
 X and Y are independently selected from the group consisting of CH.sub.2,
 O, NH, or S;
 Z is a metal chelating group;
 R.sub.1 and R.sub.2 are independently hydrogen, C.sub.1 -C.sub.9 alkyl,
 C.sub.2 -C.sub.9 alkenyl, C.sub.3 -C.sub.8 cycloalkyl, C.sub.5 -C.sub.7
 cycloalkenyl, or Ar, wherein each said alkyl, alkenyl, cycloalkyl,
 cycloalkenyl, or Ar is independently unsubstituted or substituted with one
 or more substituent(s); and
 Ar is a carbocyclic or heterocyclic moiety which is unsubstituted or
 substituted with one or more substituent(s).
 In a preferred embodiment of formula III, R.sub.1 and R.sub.2 are each
 hydrogen.
 The present invention further relates to a method for treating a glutamate
 mediated disease, disorder, or condition in a mammal, comprising
 administering to said mammal an effective amount of a compound containing
 a metabotropic glutamate receptor ligand attached to a metal chelating
 group.
 Finally, the present invention relates to a pharmaceutical composition
 comprising:
 (i) an effective amount of a compound of formula I; and
 (ii) a pharmaceutically acceptable carrier.
 INCORPORATION BY REFERENCE
 In addition to other references generally known in the art, applicants have
 previously disclosed substantial data relating to the relationship between
 glutamate and various glutamate abnormalities, and the effectiveness of
 NAALADase inhibitors generally with regard to treating ischemic insult,
 diminished neurological function, alcohol dependence, nicotine dependence,
 cancer cell and tumor growth, angiogenesis, cocaine dependence, diabetes,
 pain, and hyperalgesia. Applicants hereby incorporate by reference, as
 though set forth herein in full, such figures and discussions from U.S.
 Pat. Nos. 5,672,592, 5,795,877, 5,863,536, 5,880,112 and 5,902,817,
 allowed U.S. patent applications Ser. Nos. 08/825,997, 08/833,628,
 08/842,360 and 08/899,319 for which the issue fees have been paid, and
 International Publications Nos. WO 97/48399, WO 97/48400, WO 97/48409 and
 WO 98/53812. It would be expected that the compounds of the present
 invention would be effective as NAALADase inhibitors, and as such would
 have the same uses as the aforementioned compounds.
 DETAILED DESCRIPTION OF THE INVENTION
 Definitions
 "Attached" refers to bonding, linkage, coupling, or other molecular
 association between atoms or molecules which results in a stable chemical
 entity.
 "Chelate" or "chelation compound" refers to a coordination compound in
 which a central metal ion, such as Co.sup.2+, Ni.sup.2+, Mn.sup.2+,
 Cu.sup.2+, Zn.sup.2+, Mg.sup.2+, Fe.sup.2+, Fe.sup.3+, or Al.sup.3+, is
 attached by coordinate links to one or more nonmetal atoms in the same
 molecule, called chelating agents or ligands. Further, a bidentate or
 polydentate chelating agent forms a heterocyclic ring with the central
 metal atom as part of each ring.
 "Chelating agent," "chelating ligand," or "chelator" refers to any group
 which can chelate a metal. A chelating ligand offering one group for
 attachment to the metal is termed monodentate; two groups, bidentate;
 three or more groups, polydentate. A chelating ligand may attach to the
 metal atom by covalent or ionic bond(s). Many compounds, too numerous to
 fully enumerate here, can act as chelating ligands; common chelating
 ligands include, but are not limited to, derivatives of amines (e.g.
 ethylenediamine), aldehydes and ketones, carboxylic acids (e.g.
 ethylenediaminetetraacetic acid (EDTA)), sulfonyl- and mercapto-derivative
 groups, phosphoryls and other phorphorus derivatives, hydroxamic acid
 derivatives, and various combinations thereof.
 "Derivative" refers to a substance produced from another substance either
 directly or by modification or partial substitution.
 "Effective amount" refers to the amount required to produce the desired
 effect. "Therapeutically effective amount" refers to the amount required
 to inhibit NAALADase enzyme activity, effect neuronal activity, inhibit
 angiogenesis, and/or treat glutamate abnormality, compulsive disorder,
 prostate disease, pain and/or diabetic neuropathy.
 "Electromagnetic radiation" includes without limitation radiation having
 the wavelength of 10.sup.-20 to 10.sup.0 meters. Preferred embodiments of
 the present invention employ the electromagnetic radiation of
 gamma-radiation (10.sup.-20 to 10.sup.-13 m) x-ray radiation (10.sup.-11
 to 10.sup.-9 m), ultraviolet light (10 nm to 400 nm), visible light (400
 nm to 700 nm), infrared radiation (700 nm to 1.0 mm), and microwave
 radiation (1 mm to 30 cm).
 "Isosteres" refer to elements, molecules, or ions having different
 molecular formulae but exhibiting similar or identical physical
 properties. For example, tetrazole is an isostere of carboxylic acid
 because it mimics the properties of carboxylic acid even though they both
 have very different molecular formulae. Typically, two isosteric molecules
 have similar or identical volumes and shapes. Ideally, isosteric compounds
 should be isomorphic and able to co-crystallize. Among the other physical
 properties that isosteric compounds usually share are boiling point,
 density, viscosity and thermal conductivity. However, certain properties
 are usually different: dipolar moments, polarity, polarization, size and
 shape since the external orbitals may be hybridized differently. The term
 "isosteres" encompass "bioisosteres".
 "Bioisosteres" are isosteres which, in addition to their physical
 similarities, share some common biological properties. Typically,
 bioisosteres interact with the same recognition site or produce broadly
 similar biological effects.
 "Carboxylic acid isosteres" include without limitation direct derivatives
 such as hydroxamic acids, acylcyanamides and acylsulfonamides; planar
 acidic heterocycles such as tetrazoles, mercaptoazoles, sulfinylazoles,
 sulfonylazoles, isoxazoles, isothiazoles, hydroxythiadiazoles and
 hydroxychromes; and nonplanar sulfur- or phosphorus-derived acidic
 functions such as phosphinates, phosphonates, phosphonamides, sulphonates,
 sulphonamides, and acylsulphonamides.
 "Metabolite" refers to a substance produced by metabolism or by a metabolic
 process. "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). 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. In addition, NAAG is an agonist at group II metabotropic
 glutamate receptors, specifically mGluR3 receptors; when attached to a
 moiety capable of inhibiting NAALADase, it is expected that metabotropic
 glutamate receptor ligands will provide potent and specific NAALADase
 inhibitors.
 "NAALADase" refers to N-acetylated .alpha.-linked acidic dipeptidase, a
 membrane bound metallopeptidase which catabolizes NAAG to
 N-acetylaspartate ("NAA") and glutamate ("GLU"):
 ##STR4##
 NAALADase has recently been assigned to the M28 peptidase family and is
 also called prostate specific membrane antigen (PSM) or human glutamate
 carboxypeptidase II (GCP II), EC number 3.4.17.21. It is believed that
 NAALADase is a co-catalytic zinc/zinc metallopeptidase. 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.
 "Pharmaceutically acceptable carrier" refers to any carrier, diluent,
 excipient, suspending agent, lubricating agent, adjuvant, vehicle,
 delivery system, emulsifier, disintegrant, absorbent, preservative,
 surfactant, colorant, flavorant, or sweetener. For these purposes, the
 compounds of the present invention 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. The term parenteral as used herein includes subcutaneous,
 intravenous, intramuscular, intraperitoneal, intrathecal,
 intraventricular, intrasternal, and intracranial injection or infusion
 techniques.
 "Pharmaceutically acceptable equivalent" includes, without limitation,
 pharmaceutically acceptable salts, hydrates, metabolites, prodrugs, and
 isosteres thereof. Many pharmaceutically acceptable equivalents are
 expected to have the same or similar in vitro or in vivo activity as the
 compounds of the invention.
 "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,
 camphorsulfonate, cyclopentanepropionate, digluconate, dodecylsulfate,
 ethanesulfonate, fumarate, glucoheptanoate, glycerophosphate, hemisulfate,
 heptanoate, hexanoate, hydrochloride hydrobromide, hydroiodide,
 2-hydroxyethanesulfonate, lactate, maleate, methanesulfonate,
 2-naphthalenesulfonate, nicotinate, oxalate, thiocyanate, tosylate and
 undecanoate. 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 diamyl sulfates; long chain halides
 such as decyl, lauryl, myristyl and stearyl chlorides, bromides and
 iodides; and aralkyl halides such as benzyl and phenethyl bromides.
 "Pharmaceutically acceptable prodrug" refers to a derivative of the
 inventive compounds which undergoes biotransformation prior to exhibiting
 its pharmacological effect(s). A prodrug form is one which is not in an
 active form of the molecule as administered, but which becomes
 therapeutically active after some in vivo activity or biotransformation,
 such as metabolism, for example, enzymatic or hydrolytic cleavage. The
 prodrug is formulated with the objective(s) of improved chemical
 stability, improved patient acceptance and compliance, improved
 bioavailability, prolonged duration of action, improved organ selectivity,
 improved formulation (e.g., increased hydrosolubility), and/or decreased
 side effects (e.g., toxicity). The prodrug can be readily prepared from
 the inventive compounds using methods known in the art, such as those
 described by Burger's Medicinal Chemistry and Drug Chemistry, Fifth Ed.,
 Vol. 1, pp. 172-178, 949-982 (1995). For example, the inventive compounds
 can be transformed into prodrugs by converting one or more of the hydroxy
 or carboxy groups into esters. Preferred prodrugs of the present invention
 include compounds of formula I, II, or III, where R.sub.1, R.sub.2, or
 both are independently non-hydrogen moieties.
 "Radiosensitizer" refers to a low molecular weight compound administered to
 animals in therapeutically effective amounts to promote the treatment of
 diseases which are treatable with electromagnetic radiation. Diseases
 which are treatable with electromagnetic radiation include neoplastic
 diseases, benign and malignant tumors, and cancerous cells.
 Electromagnetic radiation treatment of other diseases not listed herein
 are also contemplated by the present invention.
 "Alkyl" refers to a branched or unbranched saturated hydrocarbon chain
 comprising a designated number of carbon atoms. For example, C.sub.1
 -C.sub.6 straight or branched alkyl hydrocarbon chain contains 1 to 6
 carbon atoms, and includes but is not limited to substituents such as
 methyl, ethyl, propyl, iso-propyl, butyl, iso-butyl, tert-butyl, n-pentyl,
 n-hexyl, and the like, unless otherwise indicated.
 "Alkenyl" refers to a branched or unbranched unsaturated hydrocarbon chain
 comprising a designated number of carbon atoms. For example, C.sub.2
 -C.sub.6 straight or branched alkenyl hydrocarbon chain contains 2 to 6
 carbon atoms having at least one double bond, and includes but is not
 limited to substituents such as ethenyl, propenyl, iso-propenyl, butenyl,
 iso-butenyl, tert-butenyl, n-pentenyl, n-hexenyl, and the like, unless
 otherwise indicated.
 "Alkoxy" refers to the group --OR wherein R is alkyl as herein defined.
 Preferably, R is a branched or unbranched saturated hydrocarbon chain
 containing 1 to 6 carbon atoms.
 "Aryl" or "aromatic" refers to an aromatic carbocyclic or heterocyclic
 group having a single ring, for example a phenyl ring; multiple rings, for
 example biphenyl; or multiple condensed rings in which at least one ring
 is aromatic, for example naphthyl, 1,2,3,4-tetrahydronaphthyl, anthryl, or
 phenanthryl, which can be unsubstituted or substituted with one or more
 other substituents as defined above. The substituents attached to a phenyl
 ring portion of an aryl moiety in the compounds of the invention may be
 configured in the ortho-, meta-, or para-orientations, with the
 para-orientation being preferred.
 "Carbocycle" or "Carbocyclic moiety" refers to an organic cyclic moiety in
 which the cyclic skeleton is comprised of only carbon atoms, whereas the
 term "heterocycle" or "heterocyclic" refers to an organic cyclic moiety in
 which the cyclic skeleton contains one or more heteroatoms selected from
 nitrogen, oxygen, or sulfur, and which may or may not include carbon
 atoms. The term "carbocycle" refers to a carbocyclic moiety containing the
 indicated number of carbon atoms. The term "C.sub.3 -C.sub.8 cycloalkyl",
 therefore, refers to an organic cyclic substituent in which three to eight
 carbon atoms form a three, four, five, six, seven, or eight-membered ring,
 including, for example, a cyclopropyl, cyclobutyl, cyclopentyl,
 cyclohexyl, cycloheptyl, or cyclooctyl ring.
 "Heterocycle" or "heterocyclic moiety" refers to a saturated, unsaturated
 or aromatic carbocyclic group having a single ring, multiple fused rings
 (for example, bicyclic, tricyclic, or other similar bridged ring systems
 or substituents), or multiple condensed rings, and having at least one
 hetero atom such as nitrogen, oxygen, or sulfur within at least one of the
 rings. This term also includes "Heteroaryl" which refers to a heterocycle
 in which at least one ring is aromatic. Any heterocyclic or heteroaryl
 group can be unsubstituted or optionally substituted with one or more
 groups, as defined above.
 "Inhibition", in the context of enzymes, refers to reversible enzyme
 inhibition such as competitive, uncompetitive and non-competitive
 inhibition. 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.sub.i, which is defined as:
 ##EQU1##
 wherein [E] is the concentration of the enzyme, [I] is the concentration of
 the inhibitor, and [EI] is the concentration of the enzyme-inhibitor
 complex formed by the reaction of the enzyme with the inhibitor. Unless
 otherwise specified, Ki as used herein refers to the affinity between the
 inventive compounds and NAALADase. "IC.sub.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. "NAALADase inhibitor" refers
 to any compound which inhibits NAALADase enzyme activity.
 "Enantiomers" are a pair of stereoisomers that are non-superimposable
 mirror images of each other. "Enantiomer-enriched" refers to a mixture in
 which one enantiomer predominates.
 "Isomers" refer to compounds having the same number and kind of atoms, and
 hence the same molecular weight, but differing in respect to the
 arrangement or configuration of the atoms.
 "Optical isomers" refer to either of two kinds of stereoisomers. One kind
 is represented by mirror-image structures called enantiomers, which result
 from the presence of one or more asymmetric carbon atoms in the compound
 (glyceraldehyde, lactic acid, sugars, tartaric acid, amino acids). The
 other kind is exemplified by diastereoisomers, which are not mirror
 images. These occur in compounds having two or more asymmetric carbon
 atoms; thus, such compounds have 2.sub.n optical isomers, where n is the
 number of asymmetric carbon atoms.
 "Stereoisomers" are isomers that differ only in the arrangement of the
 atoms in space. "Diastereoisomers" are stereoisomers which are not mirror
 images of each other.
 "Racemic mixture" means a mixture containing equal parts of individual
 enantiomers. "Non-racemic mixture" is a mixture containing unequal parts
 of individual enantiomers or stereoisomers.
 "Angiogenesis" refers to the process whereby new capillaries are formed.
 "Angiogenesis-dependent disease" includes without limitation cancer,
 rheumatoid arthritis, cardiovascular disease, neovascular diseases of the
 eye, peripheral vascular disorders, and dermatologic ulcers. "Inhibition"
 of angiogenesis may be measured by many parameters in accordance with the
 present invention and, for instance, may be assessed by delayed appearance
 of neovascular structures, slowed development of neovascular structures,
 decreased occurrence of neovascular structures, slowed or decreased
 severity of angiogenesis-dependent disease effects, arrested angiogenic
 growth, or regression of previous angiogenic growth. In the extreme,
 complete inhibition is referred to herein as prevention. In relation to
 angiogenesis or angiogenic growth, "prevention" refers to no substantial
 angiogenesis or angiogenic growth if none had previously occurred, or no
 substantial further angiogenesis or angiogenic growth if growth had
 previously occurred.
 "Animal" refers to a living organism having sensation and the power of
 voluntary movement, and which requires for its existence oxygen and
 organic food. Examples include, without limitation, a mammal such as a
 member of the human, equine, porcine, bovine, murine, canine, or feline
 species. In the case of a human, an "animal" may also be referred to as a
 "patient".
 "Anxiety" includes without limitation the unpleasant emotion state
 consisting of psychophysiological responses to anticipation of unreal or
 imagined danger, ostensibly resulting from unrecognized intrapsychic
 conflict. Physiological concomitants include increased heart rate, altered
 respiration rate, sweating, trembling, weakness, and fatigue;
 psychological concomitants include feelings of impending danger,
 powerlessness, apprehension, and tension. Dorland's Illustrated Medical
 Dictionary, W.B. Saunders Co., 27th ed. (1988).
 "Anxiety Disorder" includes without limitation mental disorders in which
 anxiety and avoidance behavior predominate. Dorland's Illustrated Medical
 Dictionary, W.B. Saunders Co., 27th ed. (1988). Examples include without
 limitation panic attack, agoraphobia, panic disorder, acute stress
 disorder, chronic stress disorder, specific phobia, simple phobia, social
 phobia, substance induced anxiety disorder, organic anxiety disorder,
 obsessive compulsive disorder, post-traumatic stress disorder, generalized
 anxiety disorder, and anxiety disorder NOS. Other anxiety disorders are
 characterized in Diagnostic and Statistical Manual of Mental Disorders
 (American Psychiatric Association 4th ed. 1994). The skilled artisan will
 recognize that there are alternative nomenclatures, nosologies, and
 classification systems for pathologic psychological conditions and that
 these systems evolve with medical scientific progress.
 "Attention Deficit Disorder" refers to a disorder characterized by
 developmentally inappropriate inattention and impulsiveness, with or
 without hyperactivity. Inattention means a failure to finish tasks
 started, easily distracted, seeming lack of attention, and difficulty
 concentrating on tasks requiring sustained attention. Impulsiveness 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.
 "Cancer" includes without limitation ACTH-producing tumors, acute
 lymphocytic leukemia, acute nonlymphocytic leukemia, cancer of the adrenal
 cortex, bladder cancer, brain cancer, breast cancer, cervix cancer,
 chronic lymphocytic leukemia, chronic myelocytic leukemia, colorectal
 cancer, cutaneous T-cell lymphoma, endometrial cancer, esophageal cancer,
 Ewing's sarcoma, gallbladder cancer, hairy cell leukemia, head and neck
 cancer, Hodgkin's lymphoma, Kaposi's sarcoma, kidney cancer, liver cancer,
 lung cancer (small and/or non-small cell), malignant peritoneal effusion,
 malignant pleural effusion, melanoma, mesothelioma, multiple myeloma,
 neuroblastoma, non-Hodgkin's lymphoma, osteosarcoma, ovary cancer, ovary
 (germ cell) cancer, pancreatic cancer, penis cancer, prostate cancer,
 retinoblastoma, skin cancer, soft-tissue sarcoma, squamous cell
 carcinomas, stomach cancer, testicular cancer, thyroid cancer,
 trophoblastic neoplasms, cancer of the uterus, vaginal cancer, cancer of
 the vulva, and Wilm's tumor.
 "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.
 "Demyelinating diseases" refers to diseases of nerve tissue involving
 damage to or removal of the myelin sheath naturally surrounding such
 tissue. Such demyelinating diseases include, for example and without
 limitation, multiple sclerosis and peripheral demyelinating disease such
 as peripheral neuropathies and Charcot-Marie-Tooth disease.
 "Disease" refers to any deviation from or interruption of the normal
 structure or function of any part, organ, or system (or combination
 thereof) of the body that is manifested by a characteristic set of
 symptoms and signs and whose etiology, pathology, and prognosis may be
 known or unknown. Dorland's Illustrated Medical Dictionary, (W.B. Saunders
 Co. 27th ed. 1988).
 "Disorder" refers to any derangement or abnormality of function; a morbid
 physical or mental state. Dorland's Illustrated Medical Dictionary, (W.B.
 Saunders Co. 27th ed. 1988).
 "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,
 without limitation, spinal cord injury, epilepsy, stroke, Alzheimer's
 disease, Parkinson's disease, Amyotrophic Lateral Sclerosis (ALS),
 Huntington's disease, schizophrenia, pain, ischemia, peripheral neuropathy
 (including but not limited to diabetic neuropathy), traumatic brain
 injury, neuronal insult, inflammatory diseases, anxiety, anxiety
 disorders, memory impairment, 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 a mammal.
 "Ischemia" refers to localized tissue anemia due to obstruction of the
 inflow of arterial blood. Global ischemia occurs when blood flow ceases
 for a period of time, such as may result from cardiac arrest. Focal
 ischemia occurs when a portion of the body, such as 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. Although 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. Much of this damage is attributed to glutamate toxicity
 and secondary consequences of reperfusion of the tissue, such as the
 release of vasoactive products by damaged endothelium, and the release of
 cytotoxic products, such as free radicals and leukotrienes, by the damaged
 tissue.
 "Memory impairment" refers to a diminished mental registration, retention
 or recall of past experiences, knowledge, ideas, sensations, thoughts or
 impressions. Memory impairment may affect short and long-term information
 retention, facility with spatial relationships, memory (rehearsal)
 strategies, and verbal retrieval and production. Common causes of memory
 impairment are age, severe head trauma, brain anoxia or ischemia,
 alcoholic-nutritional diseases, drug intoxications and neurodegenerative
 diseases. For example, memory impairment is a common feature of
 neurodegenerative diseases such as Alzheimer's disease and senile dementia
 of the Alzheimer type. Memory impairment also occurs with other kinds of
 dementia such as multi-infarct dementia, a senile dementia caused by
 cerebrovascular deficiency, and the Lewy-body variant of Alzheimer's
 disease with or without association with Parkinson's disease.
 Creutzfeldt-Jakob disease is a rare dementia with which memory impairment
 is associated. It is a spongiform encephalopathy caused by the prion
 protein; it may be transmitted from other sufferers or may arise from gene
 mutations. Loss of memory is also a common feature of brain-damaged
 patients. Brain damage may occur, for example, after a classical stroke or
 as a result of an anaesthetic accident, head trauma, hypoglycemia, carbon
 monoxide poisoning, lithium intoxication, vitamin (B.sub.1, thiamine and
 B.sub.12) deficiency, or excessive alcohol use. Korsakoff's amnesic
 psychosis is a rare disorder characterized by profound memory loss and
 confabulation, whereby the patient invents stories to conceal his or her
 memory loss. It is frequently associated with excessive alcohol intake.
 Memory impairment may furthermore be age-associated; the ability to recall
 information such as names, places and words seems to decrease with
 increasing age. Transient memory loss may also occur in patients,
 suffering from a major depressive disorder, after electro-convulsive
 therapy.
 "Enhancing memory performance" refers to improving or increasing the mental
 faculty by which to register, retain or recall past experiences,
 knowledge, ideas, sensations, thoughts or impressions.
 "Mental disorder" refers to any clinically significant behavioral or
 psychological syndrome characterized by the presence of distressing
 symptoms or significant impairment of functioning. Mental disorders are
 assumed to result from some psychological or organic dysfunction of the
 individual; the concept does not include disturbances that are essentially
 conflicts between the individual and society (social deviance).
 "Metastasis" refers to "[t]he ability of cells of a cancer to disseminate
 and form new foci of growth at noncontiguous sites (i.e., to form
 metastases)." See Hill, R. P, Chapter 11, "Metastasis", pp. 178-195 in The
 Basic Science of Oncology, Tannock et al., Eds., McGraw-Hill, New York
 (1992), herein incorporated by reference. "The transition from in situ
 tumor growth to metastatic disease is defined by the ability of tumor
 cells of the primary site to invade local tissues and to cross tissue
 barriers . . . To initiate the metastatic process, carcinoma cells must
 first penetrate the epithelial basement membrane and then invade the
 interstitial stroma . . . For distant metastases, intravasation requires
 tumor cell invasion of the subendothelial basement membrane that must also
 be negotiated during tumor cell extravasation . . . The development of
 malignancy is also associated with tumor-induced angiogenesis [which] not
 only allows for expansion of the primary tumors, but also permits easy
 access to the vascular compartment due to defects in the basement
 membranes of newly formed vessels." See Aznavoorian et al., Cancer 71:
 1368-1383 (1993), herein incorporated by reference.
 "Nervous function" refers to the various functions of the nervous system,
 which among other things provide an awareness of the internal and external
 environments of the body, make possible voluntary and reflex activities
 between the various structural elements of the organism, and balance the
 organism's response to environmental changes.
 "Nervous 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 processes, epilepsy,
 cognitive disorder, glutamate abnormality and secondary effects thereof.
 Currently, there is no known effective treatment for nervous tissue
 damage.
 "Nervous 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.
 "Pain" refers to localized sensations of discomfort, distress or agony,
 resulting from the stimulation of specialized nerve endings. It serves as
 a protective mechanism insofar as it induces the sufferer to remove or
 withdraw from the source. Dorland's Illustrated Medical Dictionary, (W.B.
 Saunders Co. 27th ed. 1988). Examples of pain include, without limitation,
 acute, chronic, cancer, burn, incisional, inflammatory, diabetic
 neuropathic and back pain.
 "Pathological gambling" refers to 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.
 "Prostate disease" refers to any disease affecting the prostate. Examples
 of prostate disease include without limitation prostate cancer such as
 adenocarcinoma and metastatic cancers of the prostate; and conditions
 characterized by abnormal growth of prostatic epithelial cells such as
 benign prostatic hyperplasia.
 "Schizophrenia" refers to a mental disorder or group mental disorders
 characterized by disturbances in form and content of thought (loosening of
 associations, delusions, hallucinations), mood (blunted, flattened,
 inappropriate affect), sense of self and relationship to the external
 world (loss of ego boundaries, dereistic thinking, and autistic
 withdrawal), and behavior (bizarre, apparently purposeless, and
 stereotyped activity or inactivity). Examples of schizophrenia include,
 without limitation, acute, ambulatory, borderline, catatonic, childhood,
 disorganized, hebephrenic, latent, nuclear, paranoid, paraphrenic,
 prepsychotic, process, pseudoneurotic, pseudopsychopathic, reactive,
 residual, schizo-affective and undifferentiated schizophrenia. Dorland's
 Illustrated Medical Dictionary, (W.B. Saunders Co. 27th ed. 1988).
 "Therapeutic window of opportunity" or "window" refers, in relation to
 stroke, to the maximal delay between the onset of ischemia and the
 initiation of efficacious therapy.
 "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" or "treatment" as used herein covers any treatment of a disease
 and/or condition in a mammal, particularly a human, and includes:
 (i) preventing a disease, disorder or condition from occurring in a mammal
 which may be predisposed to the disease, disorder and/or condition but has
 not yet been diagnosed as having it;
 (ii) inhibiting the disease, disorder or condition, i.e., arresting its
 development; and
 (iii) relieving the disease, disorder or condition, i.e., causing
 regression of the disease, disorder and/or condition.
 In relation to drug dependence, "treating" includes administering a
 compound or composition of the present invention to suppress the
 psychologic addiction or physical tolerance to the drug of abuse, and/or
 relieve and/or prevent 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.
 COMPOUNDS OF THE PRESENT INVENTION
 Formula I
 The present invention relates to a compound of formula I:
 ##STR5##
 or a pharmaceutically acceptable equivalent, wherein:
 either J and K are taken together with one or more additional atoms
 independently selected from the group consisting of C, O, S, and N in
 chemically reasonable substitution patterns to form a 3-7 membered
 saturated or unsaturated heterocyclic or carbocyclic ring, and L is --CH,
 or J, K, and L are taken together with one or more additional atoms
 independently selected from the group consisting of C, O, S, and N in
 chemically reasonable substitution patterns to form a 4-8 membered
 saturated or unsaturated, mono-, bi-, or tricyclic, hetero- or carbocyclic
 ring structure;
 Z is a metal chelating group;
 R.sub.1 and R.sub.2 are independently hydrogen, C.sub.1 -C.sub.9 alkyl,
 C.sub.2 -C.sub.9 alkenyl, C.sub.3 -C.sub.8 cycloalkyl, C.sub.5 -C.sub.7
 cycloalkenyl, or Ar, wherein each said alkyl, alkenyl, cycloalkyl,
 cycloalkenyl, or Ar is independently unsubstituted or substituted with one
 or more substituent(s); and
 Ar is a carbocyclic or heterocyclic moiety which is unsubstituted or
 substituted with one or more substituent(s).
 In a preferred embodiment of formula I, R.sub.1 and R.sub.2 are hydrogen.
 Examples of preferred combinations of J, K, and L include but are not
 limited to, the following:
 ##STR6##
 Possible substituents of said alkenyl, cycloalkyl, cycloalkenyl, and Ar
 include, without limitation, C.sub.1 -C.sub.9 straight or branched chain
 alkyl, C.sub.2 -C.sub.9 straight or branched chain alkenyl, C.sub.1
 -C.sub.9 alkoxy, C.sub.2 -C.sub.9 alkenyloxy, phenoxy, benzyloxy, C.sub.3
 -C.sub.8 cycloalkyl, C.sub.5 -C.sub.7 cycloalkenyl, hydroxy, carboxy,
 carbonyl, amino, amido, cyano, isocyano, nitro, nitroso, nitrilo,
 isonitrilo, imino, azo, diazo, sulfonyl, sulfoxy, thio, thiocarbonyl,
 thiocyano, formanilido, thioformamido, sulfhydryl, halo, haloalkyl,
 trifluoromethyl, and carbocyclic and heterocyclic moieties. Carbocyclic
 moieties include alicyclic and aromatic structures.
 Examples of useful carbocyclic and heterocyclic moieties include, without
 limitation, phenyl, benzyl, naphthyl, indenyl, azulenyl, fluorenyl,
 anthracenyl, indolyl, isoindolyl, indolinyl, benzofuranyl,
 benzothiophenyl, indazolyl, benzimidazolyl, benzthiazolyl,
 tetrahydrofuranyl, tetrahydropyranyl, pyridyl, pyrrolyl, pyrrolidinyl,
 pyridinyl, pyrimidinyl, purinyl, quinolinyl, isoquinolinyl,
 tetrahydroquinolinyl, quinolizinyl, furyl, thiophenyl, imidazolyl,
 oxazolyl, benzoxazolyl, thiazolyl, isoxazolyl, isotriazolyl, oxadiazolyl,
 triazolyl, thiadiazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl,
 trithianyl, indolizinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, thienyl,
 tetrahydroisoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl,
 quinoxalinyl, naphthyridinyl, pteridinyl, carbazolyl, acridinyl,
 phenazinyl, phenothiazinyl, and phenoxazinyl.
 Examples of useful metal chelating groups include, without limitation,
 mercapto derivatives, hydroxamic acid derivatives, phosphorus derivatives
 (particularly those of the general formula X--P(O)(OH)--R, wherein R is as
 defined above for R.sub.1), carboxyl derivatives, N-carboxyalkyl
 derivatives, aldehydes, ketones, and combinations thereof. In particular,
 useful metal chelating groups include, without limitation, derivatives of
 dicarboxylic acids, .beta.-diketones, .alpha.-hydroxycarboxylic acids,
 alkyl and aryl diamines, .alpha.- and .beta.-aminocarboxylates (including
 amino acid derivatives), thioethers, xanthates, dithiocarbamates,
 dithiocarboxylates, thioglycolates, thiols, and diphosphines. Preferred
 metal chelating ligands to be substituted for Z in Formula I herein
 include, without limitation:
 ##STR7##
 wherein:
 n is 0-3; and
 R, R.sub.3, R.sub.4, R.sub.5, and R.sub.6 are independently hydrogen,
 C.sub.1 -C.sub.9 alkyl, C.sub.2 -C.sub.9 alkenyl, C.sub.3 -C.sub.8
 cycloalkyl, C.sub.5 -C.sub.7 cycloalkenyl, or Ar, wherein each said alkyl,
 alkenyl, cycloalkyl, cycloalkenyl, or Ar is independently unsubstituted or
 substituted with one or more substituent(s); and
 Ar is a carbocyclic or heterocyclic moiety which is unsubstituted or
 substituted with one or more substituent(s).
 Examples of compounds of formula I, where J, K, and L form a heterocyclic
 ring, are shown in Table I:
 TABLE I
 ##STR8##
 Compound R.sub.1 R.sub.2 Z
 1 H H --CH.sub.2 P(O)(OH).sub.2
 2 H H ##STR9##
 3 H H ##STR10##
 4 H H ##STR11##
 5 H H --CH.sub.2 SH
 6 H H ##STR12##
 7 H H ##STR13##
 8 H H ##STR14##
 9 phenyl H --CH.sub.2 P(O)(OH).sub.2
 10 --CH.sub.3 --CH.sub.3 --CH.sub.2 P(O)(OH)CH.sub.2 CH.sub.3
 11 H --CH.sub.3 ##STR15##
 12 --CH.sub.2 CH.sub.3 phenyl --CH.sub.2 CH.sub.2 SH
 13 cyclohexyl --CH.sub.2 SH ##STR16##
 14 trifluoromethyl --NH.sub.2 ##STR17##
 15 pyridyl benzyl ##STR18##
 Preferred compounds of formula I are selected from the group consisting of:
 4-(phosphonomethyl)-2, 4-pyrrolidine dicarboxylic acid (1);
 4-[[hydroxy(phenyl)phosphinyl]methyl]-2,4-pyrrolidinedicarboxylic acid (2);
 4-[[hydroxy(phenylmethyl)phosphinyl]methyl]-2,4-pyrrolidinedicarboxylic
 acid (3);
 4-[[hydroxy(phenylethyl)phosphinyl]methyl]-2,4-pyrrolidinedicarboxylic acid
 (4);
 4-(sulfanylmethyl)-2,4-pyrrolidine dicarboxylic acid (5); and
 pharmaceutically acceptable equivalents thereof.
 Formula II
 A preferred embodiment of the present invention relates to a compound of
 formula II:
 ##STR19##
 or a pharmaceutically acceptable equivalent, wherein:
 Z is a metal chelating group;
 R.sub.1 and R.sub.2 are independently hydrogen, C.sub.1 -C.sub.9 alkyl,
 C.sub.2 -C.sub.9 alkenyl, C.sub.3 -C.sub.8 cycloalkyl, C.sub.5 -C.sub.7
 cycloalkenyl, or Ar, wherein each said alkyl, alkenyl, cycloalkyl,
 cycloalkenyl, or Ar is independently unsubstituted or substituted with one
 or more substituent(s); and
 Ar is a carbocyclic or heterocyclic moiety which is unsubstituted or
 substituted with one or more substituent(s).
 In a preferred embodiment of formula II, R.sub.1 and R.sub.2 are hydrogen.
 Possible substituents of said alkenyl, cycloalkyl, cycloalkenyl, and Ar
 include, without limitation, C.sub.1 -C.sub.9 straight or branched chain
 alkyl, C.sub.2 -C.sub.9 straight or branched chain alkenyl, C.sub.1
 -C.sub.9 alkoxy, C.sub.2 -C.sub.9 alkenyloxy, phenoxy, benzyloxy, C.sub.3
 -C.sub.8 cycloalkyl, C.sub.5 -C.sub.7 cycloalkenyl, hydroxy, carboxy,
 carbonyl, amino, amido, cyano, isocyano, nitro, nitroso, nitrilo,
 isonitrilo, imino, azo, diazo, sulfonyl, sulfoxy, thio, thiocarbonyl,
 thiocyano, formanilido, thioformamido, sulfhydryl, halo, haloalkyl,
 trifluoromethyl, and carbocyclic and heterocyclic moieties. Carbocyclic
 moieties include alicyclic and aromatic structures.
 Examples of useful carbocyclic and heterocyclic moieties include, without
 limitation, phenyl, benzyl, naphthyl, indenyl, azulenyl, fluorenyl,
 anthracenyl, indolyl, isoindolyl, indolinyl, benzofuranyl,
 benzothiophenyl, indazolyl, benzimidazolyl, benzthiazolyl,
 tetrahydrofuranyl, tetrahydropyranyl, pyridyl, pyrrolyl, pyrrolidinyl,
 pyridinyl, pyrimidinyl, purinyl, quinolinyl, isoquinolinyl,
 tetrahydroquinolinyl, quinolizinyl, furyl, thiophenyl, imidazolyl,
 oxazolyl, benzoxazolyl, thiazolyl, isoxazolyl, isotriazolyl, oxadiazolyl,
 triazolyl, thiadiazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl,
 trithianyl, indolizinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, thienyl,
 tetrahydroisoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl,
 quinoxalinyl, naphthyridinyl, pteridinyl, carbazolyl, acridinyl,
 phenazinyl, phenothiazinyl, and phenoxazinyl.
 Examples of useful metal chelating groups include, without limitation,
 mercapto derivatives, hydroxamic acid derivatives, phosphorus derivatives
 (particularly those of the general formula X--P(O)(OH)--R, wherein R is as
 defined above for R.sub.1), carboxyl derivatives, N-carboxyalkyl
 derivatives, aldehydes, ketones, and combinations thereof. In particular,
 useful metal chelating groups include, without limitation, derivatives of
 dicarboxylic acids, .beta.-diketones, .alpha.-hydroxycarboxylic acids,
 alkyl and aryl diamines, .alpha.- and .beta.-aminocarboxylates (including
 amino acid derivatives), thioethers, xanthates, dithiocarbamates,
 dithiocarboxylates, thioglycolates, thiols, and diphosphines. Preferred
 metal chelating ligands to be substituted for Z in Formula II include,
 without limitation:
 ##STR20##
 wherein:
 n is 0-3; and
 R, R.sub.3, R.sub.4, R.sub.5, and R.sub.6 are independently hydrogen,
 C.sub.1 -C.sub.9 alkyl, C.sub.2 -C.sub.9 alkenyl, C.sub.3 -C.sub.8
 cycloalkyl, C.sub.5 -C.sub.7 cycloalkenyl, or Ar, wherein each said alkyl,
 alkenyl, cycloalkyl, cycloalkenyl, or Ar is independently unsubstituted or
 substituted with one or more substituent(s); and
 Ar is a carbocyclic or heterocyclic moiety which is unsubstituted or
 substituted with one or more substituent(s).
 Examples of compounds of formula II are shown in Table II.
 TABLE II
 ##STR21##
 Compound R.sub.1 R.sub.2 Z
 16 H H --CH.sub.2 P(O)(OH).sub.2
 17 H H --CH.sub.2 P(O)(OH)CH.sub.2 CH.sub.2 CH.sub.3
 18 H H --CH.sub.2 P(O)(OH)CH.sub.2 CH.sub.2 CH.sub.2
 CH.sub.3
 19 H H ##STR22##
 20 H H ##STR23##
 21 H H ##STR24##
 22 H H --CH.sub.2 SH
 23 H H --CH.sub.2 CH.sub.2 SH
 24 H H --CH.sub.2 CH.sub.2 CH.sub.2 SH
 25 H H ##STR25##
 26 H H ##STR26##
 27 H H --NHCH.sub.2 COOH
 28 H H --CH.sub.2 NHCH.sub.2 COOH
 Preferred compounds of formula II are selected from the group consisting
 of:
 2-carboxy-.alpha.-(phosphonomethyl)-cyclopropaneacetic acid (16);
 2-carboxy-.alpha.-[[hydroxypropylphosphinyl]methyl]cyclopropaneacetic acid
 (17);
 2-carboxy-.alpha.-[[butylhydroxyphosphinyl]methyl]cyclopropaneacetic acid
 (18);
 2-carboxy-.alpha.-[[hydroxyphenylphosphinyl]methyl]cyclopropaneacetic acid
 (19);
 2-carboxy-.alpha.-[[hydroxy(phenylmethyl)phosphinyl]methyl]-cyclopropaneace
 tic acid (20);
 2-carboxy-.alpha.-[[hydroxy(2-phenylethyl)phosphinyl]methyl]-cyclopropaneac
 etic acid (21);
 2-carboxy-.alpha.-(mercaptoethyl)-cyclopropaneacetic acid (23);
 2-carboxy-.alpha.-(mercaptopropyl)-cyclopropaneacetic acid (24);
 2-carboxy-.alpha.-[2-(hydroxyamino)-2-oxoethyl]cyclopropaneacetic acid
 (25);
 2-carboxy-.alpha.-[3-(hydroxyamino)-3-oxopropyl]cyclopropaneacetic acid
 (26);
 2-carboxy-.alpha.-[(carboxymethyl)amino]cyclopropaneacetic acid (27);
 2-carboxy-.alpha.-[[(carboxymethyl)amino]methyl]cyclopropaneacetic acid
 (28); and
 pharmaceutically acceptable equivalents.
 Formula III
 Another preferred embodiment of the present invention relates to a compound
 of formula III:
 ##STR27##
 or a pharmaceuiically acceptable equivalent, wherein:
 X and Y are independently selected from the group consisting of CH.sub.2,
 O, NH, or S;
 Z is a metal chelating group;
 R.sub.1 and R.sub.2 are independently hydrogen, C.sub.1 -C.sub.9 alkyl,
 C.sub.2 -C.sub.9 alkenyl, C.sub.3 -C.sub.8 cycloalkyl, C.sub.5 -C.sub.7
 cycloalkenyl, or Ar, wherein each said alkyl, alkenyl, cycloalkyl,
 cycloalkenyl, or Ar is independently unsubstituted or substituted with one
 or more substituent(s); and
 Ar is a carbocyclic or heterocyclic moiety which is unsubstituted or
 substituted with one or more substituent(s).
 In a preferred embodiment of formula III, R.sub.1 and R.sub.2 are hydrogen.
 In another preferred embodiment of formula III, the relative
 stereochemistry of the compound is of formula IV:
 ##STR28##
 Possible substituents of said alkenyl, cycloalkyl, cycloalkenyl, and Ar
 include, without limitation, C.sub.1 -C.sub.9 straight or branched chain
 alkyl, C.sub.2 -C.sub.9 straight or branched chain alkenyl, C.sub.1
 -C.sub.9 alkoxy, C.sub.2 -C.sub.9 alkenyloxy, phenoxy, benzyloxy, C.sub.3
 -C.sub.8 cycloalkyl, C.sub.5 -C.sub.7 cycloalkenyl, hydroxy, carboxy,
 carbonyl, amino, amido, cyano, isocyano, nitro, nitroso, nitrilo,
 isonitrilo, imino, azo, diazo, sulfonyl, sulfoxy, thio, thiocarbonyl,
 thiocyano, formanilido, thioformamido, sulfhydryl, halo, haloalkyl,
 trifluoromethyl, and carbocyclic and heterocyclic moieties. Carbocyclic
 moieties include alicyclic and aromatic structures.
 Examples of useful carbocyclic and heterocyclic moieties include, without
 limitation, phenyl, benzyl, naphthyl, indenyl, azulenyl, fluorenyl,
 anthracenyl, indolyl, isoindolyl, indolinyl, benzofuranyl,
 benzothiophenyl, indazolyl, benzimidazolyl, benzthiazolyl,
 tetrahydrofuranyl, tetrahydropyranyl, pyridyl, pyrrolyl, pyrrolidinyl,
 pyridinyl, pyrimidinyl, purinyl, quinolinyl, isoquinolinyl,
 tetrahydroquinolinyl, quinolizinyl, furyl, thiophenyl, imidazolyl,
 oxazolyl, benzoxazolyl, thiazolyl, isoxazolyl, isotriazolyl, oxadiazolyl,
 triazolyl, thiadiazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl,
 trithianyl, indolizinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, thienyl,
 tetrahydroisoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl,
 quinoxalinyl, naphthyridinyl, pteridinyl, carbazolyl, acridinyl,
 phenazinyl, phenothiazinyl, and phenoxazinyl.
 Examples of useful metal chelating groups include, without limitation,
 mercapto derivatives, hydroxamic acid derivatives, phosphorus derivatives
 (particularly those of the general formula X--P(O)(OH)--R, wherein R is as
 defined above for R.sub.1), carboxyl derivatives, N-carboxyalkyl
 derivatives, aldehydes, ketones, and combinations thereof. In particular,
 useful metal chelating groups include, without limitation, derivatives of
 dicarboxylic acids, .beta.-diketones, .alpha.-hydroxycarboxylic acids,
 alkyl and aryl diamines, .alpha.- and .beta.-aminocarboxylates (including
 amino acid derivatives), thioethers, xanthates, dithiocarbamates,
 dithiocarboxylates, thioglycolates, thiols, and diphosphines. Preferred
 metal chelating ligands to be substituted for Z in Formula III herein
 include, without limitation:
 ##STR29##
 wherein:
 n is 0-3; and
 R, R.sub.3, R.sub.4, R.sub.5, and R.sub.6 are independently hydrogen,
 C.sub.1 -C.sub.9 alkyl, C.sub.2 -C.sub.9 alkenyl, C.sub.3 -C.sub.8
 cycloalkyl, C.sub.5 -C.sub.7 cycloalkenyl, or Ar, wherein each said alkyl,
 alkenyl, cycloalkyl, cycloalkenyl, or Ar is independently unsubstituted or
 substituted with one or more substituent(s); and
 Ar is a carbocyclic or heterocyclic moiety which is unsubstituted or
 substituted with one or more substituent(s).
 Examples of compounds of formula III, where Y is carbon, and R.sub.1 and
 R.sub.2 are hydrogen, are shown in Table III:
 TABLE III
 ##STR30##
 Compound X Z
 29 CH.sub.2 --CH.sub.2 P(O)(OH).sub.2
 30 O --CH.sub.2 P(O)(OH)CH.sub.2 CH.sub.3
 31 CH.sub.2 ##STR31##
 Preferred compounds of formula III are selected from the group consisting
 of:
 2-(phosphonomethyl)-bicyclo [3.1.0]hexane-2,6-dicarboxylic acid (29);
 2-[[hydroxy(ethylphosphinyl)methyl)-3-oxabicyclo
 03.1.0]hexane-2,6-dicarboxylic acid (30);
 2-[[hydroxy(phenylmethyl)phosphinyl]methyl]
 bicyclo[3.1.0]hexane-2,6-dicarboxylic acid (31); and
 pharmaceutically acceptable equivalents.
 Examples of compounds of formula III, where X is carbon, and R.sub.1 and
 R.sub.2 are hydrogen, are shown in Table IV:
 TABLE IV
 ##STR32##
 Compound Y Z
 32 O ##STR33##
 33 S ##STR34##
 34 O --CH.sub.2 P(O)(OH).sub.2
 35 S --CH.sub.2 P(O)(OH).sub.2
 36 O --CH.sub.2 SH
 37 S --CH.sub.2 SH
 38 O --CH.sub.2 P(O)(OH)CH.sub.2 CH.sub.3
 39 S --CH.sub.2 P(O)(OH)CH.sub.2 CH.sub.3
 40 O ##STR35##
 41 S ##STR36##
 Preferred compounds of formula III are selected from the group consisting
 of:
 2-oxa-4-(ethylhydroxyphosphoryl)aminobicyclo[3.1.
 0]hexane-4,6-dicarboxylate;
 2-thia-4-(ethylhydroxyphosphoryl)aminobicyclo[3.1.
 0]hexane-4,6-dicarboxylate;
 2-oxa-4-(hydroxyphosphoryl)bicyclo[3.1.0]hexane-4,6-dicarboxylate;
 2-thia-4-(hydroxyphosphoryl)bicyclo[3.1.0]hexane-4,6-dicarboxylate;
 2-oxa-4-(methylsulfanyl)bicyclo[3.1.0]hexane-4,6-dicarboxylate;
 2-thia-4-(methylsulfanyl)bicyclo[3.1.0]hexane-4,6-dicarboxylate;
 4-[[hydroxy(phenylmethyl)phosphinyl]methyl]-2-oxabicyclo[3.1.
 0]hexane-4,6-dicarboxylic acid; and
 pharmaceutically acceptable equivalents thereof.
 As already stated, the invention includes within its scope pharmaceutically
 acceptable equivalents of the inventive compounds, such as
 pharmaceutically acceptable salts and prodrugs. Examples of preferred
 pharmaceutically acceptable salts are either those with inorganic bases,
 such as sodium, potassium, calcium and aluminum hydroxides, or with
 organic bases, such as lysine, arginine, N-methyl-glucamine,
 triethylamine, triethanolamine, dibenzylamine, methylbenzylamine,
 di-(2-ethyl-hexyl)-amine, piperidine, N-ethylpiperidine,
 N,N-diethylaminoethylamine, N-ethylmorpholine, .beta.-phenethyl-amine,
 N-benzyl-.beta.-phenethylamine, N-benzyl-N,N-dimethylamine and other
 acceptable organic amines.
 Preferred prodrugs include compounds of formulas I, II, and III, where
 R.sub.1 and R.sub.2 are non-hydrogen moieties.
 Some compounds of the present invention possess one or more asymmetric
 carbon center(s) and are thus capable of existing in the form of optical
 isomers as well as in the form of racemic or non-racemic mixtures of
 optical isomers. The optical isomers can be obtained by resolution of the
 racemic mixtures according to conventional processes well known in the
 art, for example by formation of diastereoisomeric salts by treatment with
 an optically active acid or base. Examples of appropriate acids are
 tartaric, diacetyltartaric, dibenzoyltartaric, ditoluoyltartaric and
 camphorsulfonic acid and then separation of the mixture of
 diastereoisomers by crystallization followed by liberation of the
 optically active bases from these salts. A different process for
 separation of optical isomers involves the use of a chiral chromatography
 column optimally chosen to maximize the separation of the enantiomers.
 Still another available method involves synthesis of covalent
 diastereoisomeric molecules, for example, esters, amides, acetals, ketals,
 and the like, by reacting compounds used in the inventive methods and
 pharmaceutical compositions with an optically active acid in an activated
 form, an optically active diol or an optically active isocyanate. The
 synthesized diastereoisomers can be separated by conventional means such
 as chromatography, distillation, crystallization or sublimation, and then
 hydrolyzed to deliver the enantiomerically pure compound. In some cases
 hydrolysis to the parent optically active drug is not necessary prior to
 dosing the patient since the compound can behave as a prodrug. The
 optically active compounds of the present invention can likewise be
 obtained by utilizing optically active starting materials.
 It is understood that the inventive compounds encompass optical isomers as
 well as racemic and non-racemic mixtures.
 PHARMACEUTICAL COMPOSITIONS OF THE PRESENT INVENTION
 The present invention relates to a pharmaceutical composition comprising:
 (i) an effective amount of a compound of the present invention; and
 (ii) a pharmaceutically acceptable carrier.
 Preferred compounds of the present invention are set forth above.
 Preferably, the compound of the present invention is present in an
 effective amount for inhibiting NAALADase enzyme activity, treating a
 glutamate abnormality, effecting a neuronal activity, treating a
 compulsive disorder, treating a prostate disease, or inhibiting
 angiogenesis in a mammal.
 METHODS OF THE PRESENT INVENTION
 Method for Inhibiting NAALADase Enzyme Activity
 The present invention relates to a method for inhibiting NAALADase enzyme
 activity in a mammal, comprising administering to said mammal an effective
 amount of a compound of the present invention.
 NAAG is the natural substrate for the NAALADase enzyme. NAAG is also an
 agonist at group II metabotropic glutamate receptors, specifically mGluR3
 receptors. The majority of the metabotropic glutamate receptor ligands
 known are cyclized glutamate analogs. Thus, in a preferred embodiment,
 combining a metal chelating group capable of interacting with the metal
 atom(s) at the active site of NAALADase with a metabotropic glutamate
 receptor ligand, preferably an mGluR3 receptor ligand, in the form of a
 cyclized glutamate unit, is expected to provide a potent and specific
 NAALADase inhibitor.
 Method for Treating Glutamate Abnormality
 The present invention further relates to a method for treating a "glutamate
 abnormality" in a mammal, comprising administering to said mammal an
 effective amount of a compound of the present invention.
 Although not limited to any one particular theory, it is believed that the
 compounds of the present invention 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.
 Method for Treating Compulsive Disorder
 The present invention further relates to a method for treating a compulsive
 disorder, comprising administering to a patient in need of such treatment
 an effective amount of a compound of the present invention.
 Method for Effecting Neuronal Activity
 The present invention further relates to a method for effecting a neuronal
 activity in a mammal, comprising administering to said mammal an effective
 amount of the compound of the present invention.
 The neuronal activity that is effected by the inventive method may be
 selected from the group consisting of: stimulation of damaged neurons,
 promotion of neuronal regeneration, prevention of neurodegeneration and
 treatment of a neurological disorder.
 Examples of neurological disorders that are treatable by the methods of the
 present invention include without limitation: trigeminal neuralgia;
 glossopharyngeal neuralgia; Bell's Palsy; myasthenia gravis; muscular
 dystrophy; amyotrophic lateral sclerosis; progressive muscular atrophy;
 progressive bulbar inherited muscular atrophy; herniated, ruptured or
 prolapsed invertebrate disk syndromes; cervical spondylosis; plexus
 disorders; thoracic outlet destruction syndromes; peripheral neuropathies
 such as those caused by lead, dapsone, ticks, porphyria, or Guillain-Barre
 syndrome; Alzheimer's disease; and Parkinson's disease.
 The inventive method is particularly useful for treating a neurological
 disorder selected from the group consisting of: peripheral neuropathy
 caused by physical injury or disease state, traumatic brain injury,
 physical damage to the spinal cord, stroke associated with brain damage,
 demyelinating diseases and neurological disorders relating to
 neurodegeneration. Examples of demyelinating diseases include multiple
 sclerosis and peripheral demyelinating disease such as peripheral
 neuropathies and Charcot-Marie Tooth disease. Examples of neurological
 disorders relating to neurodegeneration include Alzheimer's disease,
 Parkinson's disease, and amyotrophic lateral sclerosis (ALS).
 Method for Treating Prostate Disease
 The present invention further relates to a method for treating a prostate
 disease in a mammal, comprising administering to said mammal an effective
 amount of a compound of the present invention.
 Method for Treating Cancer
 In addition to prostate cancer, other forms of cancer may be treated with
 the compounds of the present invention. The compounds of the present
 invention are particularly useful in treating cancer of tissues where
 NAALADase enzymes reside. Such tissues include the prostate as well as the
 brain, kidney and testis.
 Method for Treating Stroke
 The present invention further relates to a method for treating stroke in a
 mammal, comprising administering to said mammal an effective amount of a
 compound of the present invention more than 60 minutes following onset of
 stroke. Preferably, the compound is administered to said mammal more than
 120 minutes following the onset of stroke.
 Method for Inhibiting Angiogenesis
 It is expected that the compounds of the present invention can affect
 angiogenesis in tissues containing NAALADase. Previous research showed
 that NAALADase is enriched in synaptic plasma membranes and is primarily
 localized to neural and kidney tissue. NAALADase has also been found in
 the tissues of the prostate and testes. Additionally, previous findings
 have shown NAALADase to be present in neovasculature. Furthermore, as
 NAALADase continues to be discovered in other tissues of the body,
 NAALADase inhibitors most likely will also show efficacy in the inhibition
 of angiogenesis in those tissues.
 Accordingly, the present invention further relates to a method for
 inhibiting angiogenesis in a mammal, comprising administering to said
 mammal an effective amount of a compound of the present invention.
 Angiogenesis may be necessary for fertility or metastasis of cancer tumors,
 or may be related to an angiogenic-dependent disease. Thus, the
 angiogenic-dependent diseases treatable by the inventive methods include
 without limitation rheumatoid arthritis, cardiovascular diseases,
 neovascular diseases of the eye, peripheral vascular disorders, and
 cancerous tumor growth, invasion, and metastasis.
 Method for Treating Pain
 The present invention further relates to a method for treating pain in a
 mammal, comprising administering to said mammal an effective amount of a
 compound of the present invention.
 The compounds of the present invention are particularly effective in
 blocking tolerance to morphine and reducing the amount of morphine
 necessary for treating pain. In a preferred embodiment, the compound of
 the present invention is administered in combination with morphine.
 Method for Treating Diabetic Neuropatny
 The present invention further relates to a method for treating diabetic
 neuropathy in a mammal, comprising administering to said mammal an
 effective amount of a compound of the present invention.
 Route of Administration
 The compounds of the present invention will generally be administered by
 means well known to the ordinarily skilled artisan to a patient in the
 form of a pharmaceutical formulation. Such formulations preferably
 include, in addition to the active agent, a physiologically acceptable
 carrier and/or diluent. In the methods of the present invention, 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. The term
 parenteral as used herein includes subcutaneous, intravenous,
 intramuscular, intraperitoneal, intrathecal, intraventricular,
 intrasternal, intracranial or intraosseous injection and infusion
 techniques.
 To be effective therapeutically as central nervous system targets, the
 compounds 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.
 Dosage
 The compounds 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.
 Typically, in vitro 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.
 Administration Regimen
 For the methods of the present invention, any administration regimen well
 known to the ordinarily skilled artisan for 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.
 Combination with Other Treatments
 The compounds of the present invention may be used alone or in combination
 with other biologically active agent(s) for simultaneous, separate, or
 sequential use.
 The biologically active agent may be selected from a wide variety of
 materials, including but not limited to steroids, for example
 hydrocortisomers such as methylprednisolone; anti-inflammatory or
 anti-immune drugs, such as methotrexate, azathioprine, cyclophosphamide or
 cyclosporin A; interferon-.beta.; antibodies, such as anti-CD4 antibodies;
 agents which can reduce the risk of a second ischemic event, such as
 ticlopidine; chemotherapeutic agents; immunotherapeutic compositions;
 electromagnetic radiosensitizers; morphine for treating pain; or mixtures
 thereof.
 The compounds of the present invention 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 compound of the present invention, as well as one or
 more pharmaceutical excipients, such as wetting, emulsifying and pH
 buffering agents.
 Experimental Data
 Applicants have previously disclosed substantial data relating to the
 relationship between glutamate and various glutamate abnormalities, and
 the effectiveness of NAALADase inhibitors. See "Incorporation by
 Reference" above for further details.

EXAMPLES
 The following examples are illustrative of the present invention and are
 not intended to be limitations thereon.
 Unless otherwise indicated, all percentages are based upon 100% by weight
 of the final composition.
 The compounds of the present invention possess one or more asymmetric
 center(s) and thus can be produced as mixtures (racemic and non-racemic)
 of stereoisomers, or as individual R- and S-stereoisomers. The individual
 stereoisomers may be obtained by using an optically active starting
 material, by resolving a racemic or non-racemic mixture of an intermediate
 at some appropriate stage of synthesis, or by resolving a compound of the
 present invention. It is understood that the compounds of the present
 invention encompass optical isomers, individual stereoisomers as well as
 mixtures (racemic and non-racemic) of stereoisomers.
 Example 1
 Synthesis of Compounds
 The compounds of the present invention can be readily prepared by a variety
 of standard techniques of organic chemistry known in the art. Precursor
 compounds can also be prepared by methods known in the art. For Example,
 the following intermediate has been described by Monn, et al., in J. Med.
 Chem. 42:1027-1040, 1999:
 ##STR37##
 This intermediate can be converted to a protected acid using standard
 techniques of organic chemistry, to provide Intermediate A, which in turn
 can be converted to compounds of the invention by the pathways depicted in
 Scheme I:
 ##STR38##
 Further, Intermediate B can be prepared by the general method described by
 Monn, et al., in J. Med. Chem. 42:1027-1040, 1999, which in turn can be
 converted to compounds of the invention by the pathways depicted in Scheme
 II:
 ##STR39##
 Example 2
 A patient is suffering from a disease, disorder or condition described. The
 patient may then be administered an effective amount of a compound or a
 pharmaceutical composition of the present invention. It is expected that
 after such treatment, the patient would not suffer any significant injury
 due to, would be protected from further injury due to, or would recover
 from the disease, disorder or condition.
 The invention being thus described, it will be obvious that the same may be
 varied in many ways. Such variations are not to be regarded as a departure
 from the spirit and scope of the invention and all such modifications are
 intended to be included within the scope of the following claims.