MXPA00006283A - Prodrugs of naaladase inhibitors - Google Patents

Abstract

The present invention relates to the prodrugs of NAALADase inhibitors, pharmaceutical compositions comprising the same, and methods of using the same to treat glutamate abnormalities and prostate diseases.

Description

DEALERS OF NAALADASIDE INHIBITORS DESCRIPTION OF THE INVENTION The present invention relates to prodrugs of NAALADase inhibitors, the pharmaceutical compositions comprising the same, and methods of using them to treat glutamate abnormalities and diseases of the prostate. Glutamate Abnormalities Glutamate serves as the predominant excitatory neurotransmitter in the central nervous system (CNS). Neurons release glutamate in large amounts when deprived of oxygen, as can occur during an ischemic stroke such as a stroke or heart attack. This excess of glutamate release 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 are opened, allowing ion fluxes through their cell membranes, for example, Ca and Na + inside the cells and K + outside the cells. These ion fluxes, especially the influx of Ca 2+, cause over-stimulation of the neurons. The over-stimulated neurons secrete more glutamate, creating a domino effect which ultimately results in the death of the cell through the production of proteases, lipases and free radicals.

Excessive activation of glutamate receptors has been implicated in various neurological diseases and conditions, including epilepsy, stroke, Alzheimer's disease, Parkinson's disease, Amyotrophic Lateral Sclerosis (ALS), Huntington's disease, schizophrenia, chronic pain, ischemia and neuronal loss following hypoxia, hypoglycemia, ischemia, trauma, and nervous attack. Recent studies have also advanced a glutamatergic base for compulsive disorders, particularly drug dependence. As an example, the neurophysiological and pathological effects of ethanol have been found to be mediated through the glutamatergic system. Specifically, acute exposure to ethanol breaks down glutamatergic neurotransmission by inhibiting the ion flux through the channels in glutamate receptors, whereas chronic exposure is regulated above the number of glutamate receptors and consequently increases the ion flux. The acute removal of ethanol results in hyperexcitability and attacks in the presence of reregulated upper channels, so that post-synaptic neurons are made vulnerable to excimeric damage. Autopsy examinations of the histologically normal brains of alcoholics have shown that chronic alcoholism moderately increases the density of the NMDA subtype of glutamate receptors in the frontal cortex. This increase in regulation may represent a stage of ethanol-induced chronic neurotoxicity. As such, the neurobiological effects of alcoholism, including intoxication, withdrawal of attacks, delirium tremens, Wernicke-Korsakoff syndrome and fetal alcohol syndrome, can be understood as a spectrum of the consequences of the effect of ethanol on the glutamatergic system. In this respect, alcoholism can be considered another member of the expanding family of neurological disorders of related glutamate. The glutamatergic system has also been implicated in the behavioral effects of other drug abuse, for example, studies have shown that motor-stimulation activities of glutamatergic antagonist blockade induced by amphetamine and cocaine, and glutamatergic agonists cause the same stereotype like that produced by amphetamine. These results represent pharmacological evidence that the expression of the effect of the estexeotipico of psychomotor stimulants involve the glutamatergic system. Epidemiological studies have revealed a strong correlation between drug dependence and other compulsive disorders. Additionally, a common genetic abnormality has been found among people with alcoholism, x cocaine dependence, nicotine dependence, pathological gambling, attention deficit disorder (ADD), Tourette syndrome, compulsive overeating and obesity. It is believed that such disorders are manifestations of the effects of excitotoxicity. Efforts to prevent excitotoxicity by blocking NMDA, AMPA, Kainate receptors and MGR have shown difficulty because each receptor has multiple sites to which glutamate can bind. Many of the compositions that are effective in blocking receptors are also toxic to animals. As such, there is no effective treatment currently known for glutamate abnormalities. Prostate Cancer Prostate cancer is the main form of cancer and the second the leading cause of cancer death for men in the United States. The American Cancer Society has estimated that in 1996 alone, 317,100 new cases of prostate cancer were diagnosed and 41,400 deaths were caused through prostate cancer. The incidence rate of prostate cancer increased 65% between 1980 and 1990, and will continue to rise with improved tracking tests and longer life expectancies. While most men die of other diseases before prostate cancer had an opportunity to develop, higher prostate cancer mortality rates are expected as well as the longer man's life and the disease has more time to progress. In 1993, molecular cloning of Prostate Specific Membrane Antigen (PSMA) was reported as a marker of potential prostate carcinoma and they were hypothesized to serve as a target for imaging and cytotoxic treatment modalities for prostate cancer. PSMA antibodies, particularly labeled indium-111 and yttria-labeled PSMA antibodies have been described and clinically examined 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. In 1996, it was found that PSMA cDNA expression confers NAALADase activity. NAALADase Inhibitors NAAG and NAALADase have been implicated in several human and animal pathological conditions. For example, it has been shown that intra-hippocampal injections of NAAG evokes prolonged attack activity. More recently, it has been 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 the increased availability of synaptic glutamate increases susceptibility to attack, and suggests that x NAALADase inhibitors can 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 the concentrations of NAAG and its metabolites - NAA, glutamate and aspartate - rise two to three times in the cerebrospinal fluid of ALS patients and HCSMA dogs. In addition, NAALADase activity is significantly (two to three times) increased in the autopsy spinal cord tissue of ALS patients and dogs of HCSMA. As such, the NAALADase inhibitors can be clinically used in the repression of ALS progression if the NAAG metabolism increases is responsible for the alterations of the CSF levels of these acidic amino acids and peptides. Abnormalities in NAAG levels and NAALADase activity have also been documented in the schizophrenic autopsy brain, specifically in the prefrontal and limbic brain regions. The findings described above suggest that NAALADase inhibitors may be useful in the treatment of glutamate abnormalities. In fact, the results of the studies conducted by the inventors confirm that the NAALADase inhibitors are effective in the treatment of glutamate abnormalities (particularly stroke, Parkinson's Disease, Amyotrophic Lateral Sclerosis (ALS), spinal cord injury, alcoholism and nicotine dependence), as well as diseases of the prostate (particularly prostate cancer). While few NAALADase inhibitors have been identified, they have only been used in non-clinical search. Examples of such inhibitors include general metallopeptidase inhibitors such as o-phenanthroline, metal chelators such as EGTA and EDTA, and analogs peptides such as quisqualic acid and β-NAAG. Consequently, there is a need for the novel NAALADase inhibitors, as well as pharmaceutical compositions and methods using such novel and known NAALADase inhibitors to treat glutamate abnormalities and prostate diseases. In addition, there is a need for prodrugs of such NAALADase inhibitors to optimize pharmaceutical activity, pharmacokinetics and pharmacodynamics. The present invention relates to prodrugs of a NAALADase inhibitor. In a preferred embodiment, the NAALADase inhibitor is a hydroxyphosphinyl derivative of glutamate derived from the formula I: or a pharmaceutically acceptable salt or hydrate thereof, wherein: X is CR3R4, O or NR5; Ri and 5 are independently selected from the group consisting of hydrogen, straight or branched chain C1-C9 alkyl, straight or branched chain C2-Cg alkenyl, C3-Cs cycloaicyl, C5-C7 cycloalkenyl and Ar, wherein such Ri and R5 are independently unsubstituted or substituted with one or more substituents independently selected from the group consisting of carboxy, C3-Cs cycloalkyl, C5-C7 cycloalkenyl, halo, hydroxy, nitro, trifluoromethyl, C? Straight or branched chain Cs, straight or branched chain C2-Ce alkenyl, C1-C9 alkoxy, C2-Cg alkenyloxy, phenoxy, benzyloxy, amino, and Ar; R3 and R4 are independently selected from the group consisting of hydrogen, straight or branched chain Ci-Ce alkyl, straight or branched chain C2-C6 alkenyl, C3-Cs cycloalkyl, C5-C7 cycloalkenyl, Ar, and halo; R2 are selected from the group consisting of hydrogen, straight or branched chain C1-C9 alkyl, straight or branched chain C2-Cg alkenylene, C3-Cs cycloalkyl, C5-C7 cycloalkenyl and Ar, wherein such R2 is substituted or unsubstituted with one or more substituents independently selected from the group consisting of carboxy, C3-C8 cycloalkyl, C5-C7 cycloalkenyl, halo, hydroxy, nitro, trifluoromethyl, straight or branched chain Ci-Cs alkyl, straight or branched chain C2-C6 alkenyl, C? -Calkoxy, C2-C6 alkenyloxy, phenoxy, benzyloxy, amino, and Ar; 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 substituted or unsubstituted with one or more substituents independently selected from the group consisting of carboxy, halo, hydroxy, nitro, trifluoromethyl, cycloalkyl, Linear or branched chain Cs, straight or branched chain C2-Ce alkylene, Ci-Ce alkoxy, C2-C6 alkenyloxy, phenoxy, benzyloxy, and amino. In another preferred embodiment, the prodrug is a compound of formula II or a pharmaceutically acceptable salt or hydrate thereof, wherein: X is CR5R6, NR7 or 0; Ri and R are independently selected from the group consisting of hydrogen, straight or branched chain C1-C9 alkyl, straight or branched chain C2-Cg alkenyl, C3-Cs cycloalkyl, C5-C7 cycloalkenyl and Ari, wherein such Ri and R7 are independently unsubstituted or substituted with one or more substituents independently selected from the group consisting of carboxy, C3-C8 cycloalkyl, C5-C7 cycloalkenyl, halo, hydroxy, nitro, trifluoromethyl, C? Straight or branched chain CG, straight or branched chain C2-Ce alkenyl, C1-C9 alkoxy, C2-Cg alkenyloxy, phenoxy, benzyloxy, amino, and Ar2; R is selected from the group consisting of hydrogen, straight or branched chain C1-C9 alkyl, straight or branched chain C2-Cg alkenyl, C3-Cs cycloalkyl, C5-C7 cycloalkenyl and Ar, wherein such R2 is substituted or unsubstituted with one or more substituents independently selected from the group consisting of carboxy, C3-Cs cycloalkyl, C5-C7 cycloalkenyl, halo, hydroxy, nitro, trifluoromethyl, straight or branched chain Ci-Ce alkyl, straight or branched chain C2-Cd alkenyl, Ci-Cg alkoxy, C2-C6 alkenyloxy, phenoxy, benzyloxy, amino, and Ar2; R3 and R are independently selected from the group consisting of hydrogen, carboxy, straight or branched chain C1-C9 alkyl, straight or branched chain C2-C8 alkenyl, C3-Cs cycloalkyl, C5-C7 cycloalkenyl, and ri, with the proviso that both R3 and R are not hydrogen; wherein such R and R4 are independently unsubstituted or substituted with one or more substituents independently selected from the group consisting of carboxy, C3-Cs cycloalkyl, C5-C7 cycloalkenyl, halo, hydroxy, nitro, trifluoromethyl, Ci-alkyl Straight chain or branched chain, straight or branched chain C2-C6 alkenyl, Ci-Cβ alkoxy, C2-C6 alkenyloxy, phenoxy, benzyloxy, amino, and Ar2; R5 and R6 are independently selected from the group consisting of hydrogen, straight or branched chain C6-C6 alkyl, straight or branched chain C2-C6 alkenyl, C3-C3 cycloalkyl, C5-C7 cycloalkenyl, Ari, and halo; Ari and Ar2 are independently 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 such Ari and Ar2 are independently unsubstituted or substituted with one or more substituents independently selected from the group consisting of halo, hydroxy, nitro, trifluoromethyl, alkyl of straight or branched chain C? -C6, straight or branched chain C2-Ce alkenyl, Ci-C? alkoxy, C2-C6 alkenyloxy, phenoxy, benzyloxy, and amino. Additionally, the present invention relates to a pharmaceutical composition comprising: (i) an effective amount of a prodrug of a NAALADase inhibitor; and (ii) a pharmaceutically acceptable carrier. The present invention also relates to a method of treating an abnormality of glutamate in an animal, which comprises administering an effective amount of a prodrug of a NAALADase inhibitor to such an animal. In addition, the present invention relates to a method of effecting a neuronal activity in an animal, comprising administering an effective amount of a prodrug of a NAALADase inhibitor to such an animal. Additionally, the present invention relates to a method of treating a compulsive disorder, comprising administering an effective amount of a prodrug of a NAALADase inhibitor to a patient in need thereof. Finally, the present invention relates to a method of treating a disease of the prostate in an animal that comprises administering an effective amount of a prodrug of a NAALADase inhibitor to such an animal. BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 is a bar chart plotting the toxicity in ischemic attack (potassium cyanide and 2-deoxyglucose) against various doses of 2- (phosphonomethyl) pentanedioic acid whereby cortical cell cultures are treated. Figure 2 is a bar chart plotting the toxicity in vi tro against the various doses of NAAG to which cortical cell cultures are exposed. Figure 3 is a bar graph plotting in vitro toxicity following treatment with 2- (phosphonomethyl) pentanedioic acid, against various doses of NAAG to which cortical cell cultures are exposed. Figure 4 is a bar graph plotting the in vitro toxicity of ischemic attack against several times at which cortical cell cultures were treated with 2- (phosphonomethyl) -pentanedioic acid. Figure 5 is a bar chart plotting the volume of cortical injury in vivo against the various doses of 2- (phosphonomethyl) pentanedioic acid with which rats were treated after enduring half occlusion of the cerebral artery. Figure 6 is a bar chart plotting the volume of total cerebral infarction in vivo from rats against several times at which rats are treated with 2- (phosphonomethyl) pentanedioic acid after supporting half occlusion of the cerebral artery. Figure 7 is a bar graph plotting the increase of extracellular glutamate in vivo in striatum from rats treated with a vehicle or 2- (phosphonomethyl) pentanedioic acid after supporting half occlusion of the cerebral artery. Figure 8 is a bar chart plotting the increase of extracellular glutamate in vivo in the parietal cortex of rats treated with a vehicle or 2- (phosphonomethyl) pentanedioic acid after supporting half occlusion of the cerebral artery. Figure 9 is a bar chart plotting the increase of extracellular glutamate in vivo in the frontal cortex of rats treated with a vehicle or 2- (phosphonomethyl) pentanedioic acid after supporting half occlusion of the cerebral artery. Figure 10 (a) is a photomicrograph of the sciatic nerve of mice treated with a vehicle following cryolysis.

Figure 10 (b) is a photomicrograph of the mouse sciatic nerve treated with 2- (phosphonomethyl) pentanedioic acid following crialization. Figure 11 is a bar chart plotting the density of innervation density of striatal TH versus the treatment of mice with vehicle alone, the vehicle following MPTP, or 2- (phosphonomethyl) pentanedioic acid following MPTP. Figure 12 is a bar chart that traces the neurological function code against the treatment of rat with dynorphin A alone or 2- (phosphonomethyl) pentanedioic acid with dynorphin A. Figure 13 is a bar graph plotting the ChAT activity of spinal organotypic spinal cord cultures against the treatment of cultures with 2- (phosphonomethyl) pentanedioic acid alone, threohydroxyapartate (THA) alone, or THA with 2- (phosphonomethyl) pentanedioic acid. Figure 14 is a bar graph plotting ChAT activity of spinal organotypic spinal cord cultures against various doses of 2- (phosphonomethyl) pentanedioic acid with which the cultures were treated in the presence of THA. Figure 15 is a bar graph plotting the ingestion of ethanol from preferred alcohol rats against various doses of 2- (phosphonomethyl) pentanedioic acid with which the rats were treated. Figure 16 is a graph plotting the ingestion of cumulative nicotine of rats during a 1 hour test session, before which the rats have been trained for self-administration of nicotine and pretreated with a vehicle or 2- (phosphonomethyl) acid pentanedioic Figure 17 is a graph plotting the ingestion of cumulative food of rats during a 1 hour test session, before which the rats have been trained for self-administration of nicotine and pretreated with a vehicle or 2- (phosphonomethyl) acid pentanedioic Figure 18 is a bar graph which traces the cancer cell growth in vi tro against the various doses of quisqualic acid with which LNCAP cells were treated. Figure 19 is a bar graph plotting cancer cell growth in vi tro against the various doses of 2- (phosphonomethyl) pentanedioic acid with which LNCAP cells were treated. Definitions "Disorder of Attention Deficit" refers to a disorder characterized by the lack of attention appearance and difficulty of concentration in tasks that require uninterrupted attention and impulsivity with or without hyperactivity. The lack of attention means a failure to finish the tasks started, the easy capacity for distraction, lack of appearance of attention, and the difficulty of concentrating on tasks that require uninterrupted attention. Impulsivity means acting before thinking, difficulty taking turns, problems that organize work, and constant changing from one activity to another. Hyperactivity means difficulty remaining seated and 'still sitting, 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, dependence on drugs and eating disorders, pathological gambling, ADD and Tourette syndrome. * "Drug dependence" refers to a psychological addiction or a physical tolerance to a drug. Tolerance means a need to progressively increase the dose to produce the effect originally achieved by smaller amounts. "Eating disorders" refers to compulsive overfeeding, obesity or severe obesity. Obesity means 20% body weight above normal weight-height tables. Severe obesity means more than 100% overweight. "Glutamate abnormality" refers to any disease, disorder or condition in which glutamate is involved, including pathological conditions involving high 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 dolox, ischemia, neuronal attack 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. "Inhibition", in the context of enzymes, refers to the inhibition of the enzyme reversibie such as competitive, uncompetitive and uncompetitive inhibition. Competitive, uncompetitive and uncompetitive inhibition can be distinguished by the effects of an inhibitor on the kinetic reaction of an enzyme. Competitive inhibition occurs "when the inhibitor reversibly combines with the enzyme in such a way that it competes with a substrate, normal by binding to the active site.The affinity between the inhibitor and the enzyme can be measured by the inhibitor constant, Kx which is defined as: [E] [I] Ki = [El] where [E] is the concentration of the enzyme, [I] is the concentration of the inhibitor, and [El] 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. "IC50" is a related term used to define the concentration or amount of a compound that is required to cause 50% inhibition of the target enzyme. "Ischemia" refers to localized anemia in the tissue due to the obstruction of the arterial blood flow. Blood flow to the entire brain stops for a period of time, as may be the result of cardiac arrest. Focal ischemia occurs when a portion of the brain is deprived of its normal blood supply, such as the result of thromboembolic occlusion of a brain vessel, traumatic head injury, edema, or brain tumor. Even if transient global and focal ischemia can cause general neuronal damage. Although nervous tissue damage occurs for hours or even days following the attack of ischemia, some damage of permanent nervous tissue can develop in the initial minutes following the cessation of the flow of 2D blood to the brain. Much of this damage is attributed to the toxicity of glutamate and the secondary consequences of tissue reperfusion, such as the release of vasoactive products by damaged endothelium, and the release of cytotoxic products, such as free radicals and leukotrienes, by damaged tissue. . "Isomers" refer to compounds that have the same number and class of atoms, and of the same molecular weight, but differing with respect to the arrangement or configuration of the atoms. "Stereoisomers" are isomers that differ only in the arrangement of atoms in space. "Enantiomers" are a pair of stereoisomers they can not be superimposed on mirror images of each other. "Diastereoisomers" are stereoisomers that 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 portions of individual enantiomers or stereoisomers. "NAAG" refers to N-acetyl-aspartyl-glutamate, an important peptide component of the brain, with levels comparable to the major neurotransmitter inhibitor of gamma-aminobutyric acid (GABA). NAAG is a specific neuron, occurs in synaptic vesicles and is released in neuronal stimulation in several systems that are supposed 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 a-linked acid dipeptidase, a bound membrane metallopeptidase which catabolizes NAAG to N-acetylaspartate (NAA) and glutamate: NAAG catabolism by NAALADase NAAG NAA GLU The NAALADase shows a high affinity for NAAG with a Km of 540 Nm. If NAAG is a bioactive peptide, then NAALADase can serve to not activate the synaptic action of NAAG. Alternatively, if NAAG functions as a precursor for glutamate, the primary function of NAALADase may be to regulate the availability of synaptic glutamate. "Nervous Function" refers to the various functions of the nervous system, which among other things provide a knowledge of the internal and external environment of the body, makes voluntary and reflex activities possible among the various structural elements of the organism, and balances the response of the body. organism to changes in the environment. "Nervous attack" refers to any damage to the nervous tissue and any resulting disability or death. The cause of nervous attack can be metabolic, toxic, neurotoxic, iatrogenic, thermal or chemical, and includes without limitation ischemia, hypoxia, stroke, trauma, surgery, pressure, mass effect, hemorrhage, radiation, vasospasm, neurodegenerative disease, process neurodegenerative, infection, Parkinson's disease, ALS, process of myelination / demyelination, epilepsy, cognitive disorder, glutamate abnormality and side effects thereof. There is no effective treatment currently known, for nerve tissue damage. "Nervous tissue" refers to the various components that make up the nervous system, including without limitation the neurons, neural support cells, glia, Schwann cells, vasculature contained within and providing these structures, the central nervous system, the brain , the brainstem, the spinal cord, the union of the central nervous system with the peripheral nervous system, the peripheral nervous system and related structures. "Neuroprotective" refers to the effect of reducing, stopping or relieving improving nervous attacks, and protecting, resuscitating or rekindling nervous tissues that have suffered nervous attack. "Pathological gambling" is a condition characterized by a concern with playing. Similar to the abuse of psychoactive substance, its effects include development of tolerance with a need to progressively play larger amounts of money, withdrawal symptoms, and continued play despite the severe negative effects on family and occupation. "Pharmaceutically acceptable salt" refers to a salt of the inventive compounds that possesses the desired pharmacological activity and which is not biologically or otherwise undesirable. The salt can be formed with inorganic acids such as acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate butyrate, citrate, camforate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, fumarate, glucoheptanoate, glycerophosphate, hemisulfate heptanoate, hexanoate. , hydrochloride hydrochloride, iodohydrate, 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 with organic bases such as the salts of dicyclohexylamine, N-methyl-D -glucamine, and salts with amino acids such as arginine and lysine. Groups containing basic nitrogen can be quartered with agents including lower alkyl halides such as methyl, ethyl, propyl and butyl chlorides, bromides and iodides; dialkylsulfates such as dimethyl, diethyl, dibutyl and diamyl sulfates; long chain halides such as decyl, lauryl, myristyl and stearyl chlorides, ides and iodides; and aralkyl halides such as benzyl and phenethyl ides. "Prodrugs" refers to those derived from drug molecules that undergo biotransformation before exhibiting their pharmacological effects. The carrier-linked drugs are drugs linked to a portion of the carrier by a labile bridge. A special group of carrier-linked prodrugs are specific sites of chemical release systems. Bioprecursors are prodrugs that do not contain a carrier group and are activated by the metabolic creation of a functional group. Macromolecular prodrugs are synthetic conjugates of drugs covalently bound to proteins, polypeptides, polysaccharides, and other biodegradable polymers. Another group of prodrugs is provided by drugs coupled to monoclonal antibodies.

"Tourette syndrome" refers to an autosomal multiple tic disorder characterized by compulsive blasphemy, 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 start as nerve involvement. Complex tics often resemble fragments of normal behavior. "Treatment" refers to: (i) preventing a disease, disorder or condition from occurring in an animal which may predispose to the disease, disorder and / or condition but has not yet been diagnosed as having it; (ü) inhibit the disease, disorder or condition, that is, stop its development; and (iii) alleviating the disease, disorder or condition, i.e., causing regression of the disease, disorder and / or condition. Regarding the dependence of the drug, "treatment" refers to suppressing psychological addiction or physical tolerance to the drug of abuse, and alleviating or preventing a withdrawal syndrome that is the result of drug dependence. "Withdrawal syndrome" refers to an X disorder characterized by unfavorable physical changes that occur when the drug is discontinued or when its effect is neutralized by a specific antagonist. COMPOSITIONS OF THE PRESENT INVENTION The present invention relates to a prodrug of a NAALADase inhibitor. Preferred NAALADASA INHIBITORS Since NAALADase is a metallopeptidase, the main useful NAALADase inhibitor drugs include small molecule compounds with functional groups known to inhibit etalopeptidases, such as hydroxyphosphinyl derivatives. According to the scientific literature, the glutamate portion plays a more critical role than the aspartate portion in the recognition of NAAG by NAALADase. As such, a preferred NAALADase inhibitor is a hydroxyphosphinyl derivative of glutamate derived from the formula I: or a pharmaceutically acceptable salt or hydrate thereof, in where: X is CR3R4, 0 or NR5; Ri and R5 are independently selected from the group consisting of hydrogen, branched-chain straight-chain C1-C9 alkyl, branched or straight-chain C2-Cg alkenyl, C3-Ca cycloalkyl, C5-C7 cycloalkenyl, and Ar, wherein such Ri and R5 are independently unsubstituted or substituted with one or more substituents independently selected from the group consisting of carboxy, C3-C8 cycloalkyl, C5-C7 cycloalkenyl, halo, hydroxy, nitro, trifluoromethyl, C? C6 straight or branched chain, straight or branched chain C2-C2 alkenyl, Ci-Cg alkoxy, C2-Cg alkenyloxy, phenoxy, benzyloxy, amino, and Ar; R2 are selected from the group consisting of hydrogen, straight or branched chain Ci-Cg alkyl, straight or branched chain C2-Cg alkenylene, C3-Cs cycloalkyl, C5-C7 cycloalkenyl and Ar, wherein such R2 is substituted or unsubstituted with one or more substituents independently selected from the group consisting of carboxy, C3-Ca cycloalkyl, C5-C7 cycloalkenyl, halo, hydroxy, nitro, trifluoromethyl, straight or branched chain Ci-Ce alkyl, C2-CT alkenyl straight or branched chain, Ci-Ce alkoxy, C2-C6 alkenyloxy, phenoxy, benzyloxy, amino, and Ar; R3 and R are independently selected from the group consisting of hydrogen, straight or branched chain Ci-Ce alkyl, straight or branched chain C2-C2 alkenyl, C3-Ca cycloalkyl, Cs-C7 cycloalkenyl, Ar, and halo; 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 such Ar is substituted or unsubstituted with one or more substituents independently selected from the group consisting of carboxy, halo, hydroxy, nitro, trifluoromethyl, straight or branched chain C-Ce alkyl, straight or branched chain C2-C6 alkenyl, C1-C6 alkoxy, C2-C6 alkenyloxy, phenoxy, benzyloxy, and amino. Preferably, X is CH2. More preferably, R_. it is substituted with carboxy. Still more preferably, Ri is hydrogen, straight or branched chain C1-C4 alkyl, straight or branched chain C2-C4 alkenyl, C3-Cs cycloalkyl, Cs-C7 cycloalkenyl, benzyl or phenyl, wherein R is substituted or unsubstituted with one or more substituents independently selected from the group consisting of carboxy, C3-C8 cycloalkyl, C5-C7 cycloalkenyl, halo, hydroxy, nitro, trifluoromethyl, straight or branched chain C6-6 alkyl, straight-chain or branched C2-C6 alkenyl, C?-C4 alkoxy, C2-C4 alkenyloxy, phenoxy, benzyloxy, amino, benzyl, and phenyl; and R2 is C? -C2 alkyl.

More preferably, the hydroxyphosphinyl derivative of glutamate derivative is selected from the group consig of: 2- (phosphonomethyl) pentanedioic acid; 2- (phosphonomethyl) succinic acid; 2- [[(2-carboxyethyl) hydroxyphosphinyl] methyl] -pentanedioic acid; 2- [[Methylhydroxyphosphinyl] methyl] pentanedioic acid; 2- [[ethylhydroxyphosphinyl] methyl] pentanedioic acid; - 2- [[propylhydroxyphosphinyl] methyl] pentanedioic acid; 2- [[butylhydroxyphosphinyl] methyl] pentanedioic acid; 2- [cyclohexylhydroxyphosphinyl] ethyl] pentanedioic acid; 2- [[(cyclohexyl) methylhydroxyphosphinyl] methyl] -pentane acid; 2- [[phenylhydroxyphosphinyl] methyl] pentanedioic acid; 2- [(benzylhydroxyphosphinyl) methyl] pentane-dioic acid; 2- [[(phenylmethyl) hydroxyphosphinyl] methyl] -pentanedioic acid; 2- [[(phenylethyl) hydroxyphosphinylmethyl] pentanedioic acid; "2- [[(phenylpropyl) hydroxyphosphinyl] methyl] -'-pentanedioic acid; 2 - [[(phenylbutyl) hydroxyphosphinyl] methyl] -pentanedioic acid; 2- [[(4-methylbenzyl) hydroxyphosphinyl] methyl] -pentanedioic acid; 2- [[(4-Fluorobenzyl) hydroxyphosphinyl] methyl] -pentanedioic acid, 2- [(2-fluorobenzyl) hydroxyphosphinyl] methyl] -pentanedioic acid, 2- [[(pentafluorobenzyl) hydroxyphosphinyl] -methyl] pentanedioic acid; - [[(methoxybenzyl) hydroxyphosphinyl] methyl] -pentanedioic acid 2- [[(2,3-trimethoxyphenyl) hydroxyphosphinyl] -methyl] pentanedioic acid 2- [[(phenylpropi1-2-enyl) hydroxyphosphinyl] -methyl] ] pentanedioic acid 2- [[(2-fluorobenzyl) hydroxyphosphinyl] methyl] -pentanedioic acid 2- [[((hydroxy) phenylmethyl) hydroxyphosphinyl] • methyl] pentanedioic acid 2- [[(3-methylbenzyl) hydroxyphosphinyl]] methyl] -pentanedioic, 2- [[(4-fluorophenyl) hydroxyphosphinyl] methyl] pentanedioic acid; 2- [[(3-trifluoromethylbenzyl) hydroxyphosphinyl] -methyl] pentanedioic acid; and pharmaceutically acceptable salts and hydrates thereof In another preferred embodiment, formula I, R2 is C3-Cg alkyl; Rx 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-alkyl? -C4 straight or branched chain subuted with 2-indolyl, 3-indolyl, 4-indolyl, 2-furyl, 3-furyl, tetrahydrofuranyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl or 4-pyridyl; or Ri is 1-naphthyl, 2-naphthyl, or straight or branched chain C 1 -C 4 alkyl subuted with 1-naphthyl or 2-naphthyl. Preferred compounds of this embodiment include: 2- [(methylhydroxyphosphinyl) methyl] hexanedioic acid; 2- [benzylhydroxyphosphinyl) methyl] hexanedioic acid; 2- [(Methylhydroxyphosphinyl) methyl] heptanedioic acid; 2- [(benzylhydroxyphosphinyl) methyl] heptanedioic acid; 2- [(Methylhydroxyphosphinyl) methyl] octanedioic acid; 2- [(benzylhydroxyphosphinyl) methyl] octane-dioic acid; 2- [(Methylhydroxyphosphinyl) methyl] nonanodioic acid; 2- [(benzylhydroxyphosphinyl) methyl] nonanodioic acid; 2- [(Methylhydroxyphosphinyl) methyl] decanedioic acid; 2- [(benzylhydroxyphosphinyl) methyl] decano-dioic acid; 2- [[(2-pyridyl) methylhydroxyphosphinyl] methyl] -pentanedioic acid; 2- [[(3-pyridyl) methylhydroxyphosphinyl] methyl] -pentanedioic acid; 2- [[(4-pyridyl) methylhydroxyphosphonyl] methyl] -pentanedioic acid; 2- [[(3-pyridyl) ethylhydroxyphosphinyl] methyl] -pentanedioic acid; 2- [[(3-pyridyl) propylhydroxyphosphinyl] methyl] -pentanedioic acid; 2- [(tetrahydrofuranyl) methylhydroxyphosphinyl] -methyl] -pentanedioic acid; 2- [[(tetrahydrofuranyl) ethylhydroxyphosphinyl] -methyl] pentanedioic acid; 2- [[(Tetrahydrofuranyl) propylhydroxy-phosphinyl] methyl] pentanedioic acid; 2- [[(2-tetrahydropyranyl) hydroxyphosphinyl] -methyl] pentanedioic acid; 2- [[(3-tetrahydropyranyl) hydroxyphosphinyl] -methyl] pentanedioic acid; 2- [[(4-tetrahydropyranyl) hydroxyphosphinyl] methyl] pentanedioic acid; 2- [[(2-indolyl) methylhydroxyphosphinyl] -methyl] pentanedioic acid; 2- [[(3-indolyl) methylhydroxyphosphinyl] methyl] -pentanedioic acid; 2- [[(4-indol11) methylhydroxyphosphinyl] methyl] -pentanedioic acid; 2- [[(3-indolyl) ethylhydroxyphosphinyl] methyl] -pentanedioic acid; 2- [[(3-indolyl) propylhydroxyphosphinyl] methyl] -pentanedioic acid; 2- [[(2-thienyl) methylhydroxyphosphinyl] methyl] -pentanedioic acid; 2- [(3-thienyl) methylhydroxyphosphinyl] methyl] -pentanedioic acid; 2 - [[(4-thienyl) methylhydroxyphosphinyl] methyl] pentanedioic acid; 2 - [[(3-thienyl) ethylhydroxyphosphinyl] methyl] -pentanedioic acid; 2- [[(3-thienyl) propylhydroxyphosphinyl] methyl] -pentanedioic acid; 2- [[(2-pyridyl) hydroxyphosphinyl] methyl] 'pentanedioic acid; 2- [[(3-pyridyl) hydroxyphosphinyl] methyl] pentanedioic acid; 2- [[(4-pyridyl) hydroxyphosphinyl] methyl] -pentanedioic acid; 2- [[(tetrahydrofuranyl) hydroxyphosphinyl] -methyl] pentanedioic acid; 2- [[(2-indolyl) hydroxyphosphinyl] methyl] -pentanedioic acid; 2- [[(3-indolyl) hydroxyphosphinyl] methyl] pentanedioic acid; 2- [[(4-indolyl) hydroxyphosphinyl] methyl] pentane-dioic acid; 2- [[(2-thienyl) hydroxyphosphinyl] methyl] pentanedioic acid; 2- [[(3-thienyl) hydroxyphosphinyl] methyl] pentanedioic acid; 2- [[(4-thienyl) hydroxyphosphinyl] methyl] pentanedioic acid; 2- [[(1-naphthyl) hydroxyphosphinyl] methyl] pentanedioic acid; 2- [[(2-naphthyl) hydroxyphosphinyl] methyl] pentane-dioic acid; 2- [[(1-naphthyl) methylhydroxyphosphinyl] methyl] -pentanedioic acid; 2- [[(2-naphthyl) methylhydroxyphosphinyl] methyl] pentanedioic acid; 2- [[(1-naphthyl) ethylhydroxyphosphinyl] methyl] x pentanedioic acid; 2- [[(2-naphthyl) ethylhydroxyphosphinyl] methyl] -pentanedioic acid; 2- [[(1-naphthyl) propylhydroxyphosphinyl] methyl] -pentanedioic acid; 2 - [[(2-naphthyl) propylhydroxyphosphinyl] methyl] -pentanedioic acid; 2 - [[(l-naphthyl) butylhydroxyphosphinyl] methyl] -pentanedioic acid; 2- [[(2-naphthyl) butylhydroxyphosphinyl] methyl] -pentanedioic acid; and pharmaceutically acceptable salts and hydrates thereof. In another preferred embodiment of formula I, X is CH2 and R2 is selected from the group consisting of hydrogen, straight or branched chain Ci-Cg alkyl, straight or branched chain C2-Cg alkenyl, C3-Cs cycloalkyl , C5-C7 cycloalkenyl, benzyl and phenyl, wherein R2 is substituted or unsubstituted with one or more substituents independently selected from the group consisting of C3-Ca cycloalkyl, C5-C7 cycloalkenyl, C6-C6 alkyl straight or branched chain, straight or branched chain C 2 -C 2 alkenyl, C 1 -C 4 alkoxy, and phenyl. More preferably, Ri is hydrogen, straight or branched chain C 1 -C 4 alkyl, C 1 -C 4 alkenyl of x straight or branched chain, C 3 -C 7 cycloalkyl, C 5 -C 7 cycloalkenyl, benzyl or phenyl, wherein Ri is substituted or unsubstituted with one or more substituents independently selected from the group consisting of carboxy, C3-C8 cycloalkyl, C5-C7 cycloalkenyl, halo, hydroxy, nitro, trifluoromethyl, straight or branched chain Ci-Cs alkyl, straight or branched chain C 2 -C 6 alkenyl, C 1 -C alkoxy, C 2 -C 4 alkenyloxy, phenoxy, benzyloxy, amino, benzyl, and phenyl. More preferably, the hydroxyphosphinyl derivatives of glutamate derivative is selected from the group consisting of: 3- (methylhydroxyphosphinyl) -2-phenylpropanoic acid; 3- (ethylhydroxyphosphinyl) -2-phenylpropanoic acid; 3- (propylhydroxyphosphinyl) -2-phenylpropanoic acid; 3- (butylhydroxyphosphinyl) -2-phenylpropanoic acid; 3- (cyclohexylhydroxyphosphinyl) -2-phenylpropanoic acid; 3- ((cyclohexyl) methylhydroxyphosphinyl) -2-phenylpropanoic acid; 3- (phenylhydroxyphosphinyl) -2-phenylpropanoic acid; 3- (benzylhydroxyphosphinyl) -2-phenylpropanoic acid; 3- (phenylethylhydroxyphosphinyl) -2-phenylpropanoic acid; 3- (phenylpropylhydroxyphosphinyl) -2- x phenylpropanoic acid, 3- (phenylbutylhydroxyphosphinyl) -2-phenylpropanoic acid; 3- ((2,3-trimethoxyphenyl) -3-hydroxyphosphinyl) -2-phenylpropanoic acid 3- (phenylprop-2-enylhydroxyphosphinyl) -2-phenylpropanoic acid; 3- (benzylhydroxyphosphinyl) -2-ethylpropanoic acid; 3- (benzylhydroxyphosphinyl) -2-propylpropanoic acid; 3- (benzylhydroxyphosphinyl) -2-butylpropanoic acid; 3- (benzylhydroxyphosphinyl) -2-cyclohexyl-propanoic acid; 3- (benzylhydroxyphosphinyl) -2- (cyclohexyl) -methylpropanoic acid; 3- (benzylhydroxyphosphinyl) -2-phenylpropanoic acid; 3- (benzylhydroxyphosphinyl) -2-benzylpropanoic acid; 3- (benzylhydroxyphosphinyl) -2-phenylethyl-propanoic acid; 3- (benzylhydroxyphosphinyl) -2-phenylpropyl-propanoic acid; 3- (benzylhydroxyphosphinyl) -2-phenylbutyl-propanoic acid; 3- (Benzylhydroxyphosphinyl) -2- (2,3, -trimethoxy-phenyl) -propanoic acid; 3- (benzylhydroxyphosphinyl) -2-phenylprop-2-enylpropanoic acid; and pharmaceutically acceptable salts and hydrates thereof. In a further embodiment of the formula I, at least one of Ri and R2 is 2-indolyl, 3-indolyl, 4-indolyl, 2-furyl, 3-furyl, tetrahydrofuranyl, tetrahydropyranyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, or straight or branched chain C 1 -C 4 alkyl substituted with 2-indι-lyl 3-indolyl, 4-indolyl, 2-furyl, 3-furyl, tetrahydrofuranyl, -thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl or 4-pyridyl; or Ri is 1-naphthyl, 2-naphthyl, or straight or branched chain C? ~C alkyl substituted with 1-naphthyl or 2-naphthyl. Preferred compounds of this embodiment include: 3- [(2-pyridyl) methylhydroxyphosphinyl] -2-phenylpropanoic acid; 3- [(3-pyridyl) methylhydroxyphosphinyl-3-2-phenylpropanoic acid; 3- [(4-pyridyl) methylhydroxyphosphinyl] -2-phenylpropanoic acid; 3- [(3-pyridyl) ethylhydroxyphosphinyl] -2-phenylpropanoic acid; 3- [(3-pyridyl) propylhydroxyphosphinyl] -2-phenylpropanoic acid; 3- [(tetrahydrofuranyl) methylhydroxyphosphinyl] -2-phenylpropanoic acid; 3- [(tetrahydrofuranyl) ethylhydroxyphosphinyl] -2-phenylpropanoic acid; 3- (tetrahydrofuranyl) propylhydroxyphosphinyl] -2-phenylpropanoic acid; 3- [(2-indolyl) methylhydroxyphosphinyl] -2-phenylpropanoic acid; 3- [(3-indolyl) methylhydroxyphosphinyl] -2-phenylpropanoic acid; 3- [(4-indolyl) methylhydroxyphosphinyl] -2-phenylpropanoic acid; 3- (3-indolyl) ethylhydroxyphosphinyl] -2-phenylpropanoic acid; 3- [(3-indolyl) propylhydroxyphosphinyl] -2-phenylpropanoic acid; 3- [(2-thienyl) methylhydroxyphosphinyl] -2-phenylpropanoic acid; 3- (3-thienyl) methylhydroxyphosphinyl] -2-phenylpropanoic acid; 3 - [(4-thienyl) methylhydroxyphosphinyl] -2-phenylpropanoic acid; 3- [(3-thienyl) ethylhydroxyphosphinyl] -2-phenylpropanoic acid; 3- [(3-thienyl) propylhydroxyphosphinyl] -2-phenyl-xpropanoic acid; 3- (benzylhydroxyphosphonoyl) -2- (2-pyridyl) methylpropanoic acid; 3- (benzylhydroxyphosphinyl) -2- (3-pyridyl) methylpropanoic acid; 3- (benzylhydroxyphosphinyl) -2- (4-pyridyl) methylpropanoic acid; 3- (benzylhydroxyphosphinyl) -2- (3-pyridyl) ethylpropanoic acid; 3- (benzylhydroxyphosphinyl) -2- (3-pyridyl) -propylpropanoic acid; 3- (benzylhydroxyphosphinyl) -2- (tetrahydro-furanyl) methylpropanoic acid; 3- (benzylhydroxyphosphinyl) -2- (tetrahydro-furanyl) ethylpropanoic acid; 3- (benzylhydroxyphosphinyl) -2- (tetrahydro-furanyl) propylpropanoic acid; 3- (benzylhydroxyphosphinyl) -2- (2-indolyl) methylpropanoic acid; 3- (benzylhydroxyphosphinyl) -2- (3-indolyl) methylpropanoic acid; 3- (benzylhydroxyphosphinyl) -2- (4-indolyl) methylpropanoic acid; 3- (benzylhydroxyphosphinyl) -2- (3-indolyl) ethyl-propanoic acid; 3- (benzylhydroxyphosphinyl) -2- (3-indolyl) -propylpropanoic acid; 3- (benzylhydroxyphosphinyl) -2- (2-thienyl) methylpropanoic acid; 3- (benzylhydroxyphosphinyl) -2- (3-thienyl) methylpropanoic acid; 3- (benzylhydroxyphosphinyl) -2- (4-thienyl) methylpropanoic acid; 3- (benzylhydroxyphosphinyl) -2- (3-thienyl) ethylpropanoic acid; 3- (benzylhydroxyphosphinyl) -2- (3-thienyl) propylpropanoic acid, 3 - ((1-naphthyl) hydroxyphosphinyl) -2-phenylpropanoic acid; 3- ((2-naphthyl) hydroxyphosphinyl) -2-phenylpropanoic acid; 3- ((1-naphthyl) methylhydroxyphosphinyl) -2-phenylpropanoic acid; 3- ((2-naphthyl) methylhydroxyphosphinyl) -2-phenylpropanoic acid; 3- ((1-naphthyl) ethylhydroxyphosphinyl) -2-phenylpropanoic acid; 3- ((2-naphthyl) ethylhydroxyphosphinyl) -2-phenylpropanoic acid; 3- ((1-naphthyl) propylhydroxyphosphinyl) -2-phenyl-xpropanoic acid; 3- ((2-naphthyl) propylhydroxyphosphinyl) -2-phenylpropanoic acid; 3 - ((l-naphthyl) butylhydroxyphosphinyl) -2-phenylpropanoic acid; 3- ((2-naphthyl) butylhydroxyphosphinyl) -2-phenylpropanoic acid; and pharmaceutically acceptable salts and hydrates thereof. When X has 0, R2 is preferably substituted with carboxy. Exemplary compounds of this embodiment include: 2- [[methylhydroxyphosphinyl] oxy] pentanedioic acid; 2- [[ethylhydroxyphosphinyl] oxy] pentanedioic acid; 2- [[propylhydroxyphosphinyl] oxy] pentanedioic acid; 2- [[butylhydroxyphosphinyl] oxy] pentanedioic acid; 2- [[cyclohexylhydroxyphosphinyl] oxy] -pentanedioic acid; 2 - [[(cyclohexyl) methylhydroxyphosphinyl] oxy] -pentanedioic acid; 2- [[phenylhydroxyphosphinyl] oxy] pentanedioic acid; 2- [[benzylhydroxyphosphinyl] oxy] pentanedioic acid; 2 - [[Phenylethylhydroxyphosphinyl] oxy] -pentanedioic acid; 2- [[Phenylpropylhydroxyphosphinyl] oxy] -pentanedioic acid; 2- [[phenylbutylhydroxyphosphinyl] oxy] pentanedioic acid; 2- [[(4-methylbenzyl) hydroxyphosphinyl] oxy] -pentanedioic acid; 2- [[(4-fluorobenzyl) hydroxyphosphinyl] oxy] pentanedioic acid; 2- [[(2-fluorobenzyl) hydroxyphosphinyl] oxy] pentanedioic acid; 2- [[(pentafluorobenzyl) hydroxyphosphinyl] oxy] pentanedioic acid; 2- [[(methoxybenzyl) hydroxyphosphinyl] oxy] pentanedioic acid; 2- [[(2,3, -trimethoxyphenyl) hydroxyphosphinyl] oxy] pentanedioic acid; 2- [[(1-naphthyl) hydroxyphosphinyl] oxy] pentanedioic acid; 2 - [[(2-naphthyl) hydroxyphosphinyl] oxy pentanedioic acid; [(1-naphthyl) methylhydroxyphosphinyl] oxy] pentanedioic acid; 2- [[(2-naphthyl) methylhydroxyphosphinyl] oxy] -pentanedioic acid; [(1-naphthyl) ethylhydroxyphosphinyl] oxy] pentanedioic acid; 2- [[(2-naphthyl) ethylhydroxyphosphinyl] oxy] -pentanedioic acid; 2- [[(1-naphthyl) propylhydroxyphosphinyl] oxy] -pentanedioic acid; 2- [[(2-naphthyl) propylhydroxyphosphinyl] oxy] -pentanedioic acid; 2- [[(l-naphthyl) butylhydroxyphosphinyl] oxy] -pentanedioic acid; 2 - [[(2-naphthyl) butylhydroxyphosphinyl] oxy] -pentanedioic acid; 2- [[(Phenylprop-2-enyl) hydroxyphosphinyl] oxy] -pentanedioic acid; 2- [[benzylhydroxyphosphinyl] oxy] pentanedioic acid; 2- [[((hydroxy) phenylmethyl) hydroxyphosphinyl] -oxy] pentanedioic acid; 2- [[(3-methylbenzyl) hydroxyphosphinyl] oxy] -pentanedioic acid; 2- [[(4-fluorophenyl) hydroxyphosphinyl] oxy] -pentanedioic acid; 2- [[(2-fluorobenzyl) hydroxyphosphinyl] oxy] -pentanedioic acid; 2- (phosphono) oxy] pentanedioic acid; 2- [[(3-trifluoromethyl-1-benzyl) hydroxy-phosphinyl] -oxy] -pentanedioic acid; 2- [[Methylhydroxyphosphinyl] oxy] -2-phenylethanoic acid; 2- [[ethylhydroxyphosphinyl] oxy] -2-phenylethanoic acid; 2- [[propylhydroxyphosphinyl] oxy] -2-phenylethanoic acid; 2- [[butylhydroxyphosphinyl] oxy] -2-phenyl-ethanoic acid; 2- [[cyclohexylhydroxyphosphinyl] oxy] -2-phenylethanoic acid; 2- [[(cyclohexyl) methylhydroxyphosphinyl] oxy] -2-phenylethanoic acid; 2- [[phenylhydroxyphosphinyl] oxy] -2-phenyl-ethanoic acid; 2- [[benzylhydroxyphosphinyl] oxy] -2-phenyl-ethanoic acid; 2- [[Phenylethylhydroxyphosphinyl] oxy] -2-phenylethanoic acid; 2- [[Phenylpropylhydroxyphosphinyl] oxy] -2.-phenylethanoic acid; 2- [[phenylbutylhydroxyphosphinyl] oxy] -2-phenyl-ethanoic acid; 2- [[(2,3-trimethoxyphenyl) -3-hydroxy-phosphinyl] oxy] -2-phenylethanoic acid; 2- [[(1-naphthyl) hydroxyphosphinyl] oxy] -2-phenyl-ethanoic acid; 2- [[(2-naphthyl) hydroxyphosphinyl] oxy] -2-phenyl-ethanoic acid; 2- [[(1-naphthyl) methylhydroxyphosphinyl] oxy] -2-phenylethanoic acid; 2- [[(2-naphthyl) methylhydroxyphosphinyl] oxy] -2-phenylethanoic acid; 2- [[(1-naphthyl) ethylhydroxyphosphinyl] oxy] -2-phenylethanoic acid; 2 - [[(2-naphthyl) ethylhydroxyphosphinyl] oxy] -2-phenylethanoic acid; 2- [[(1-naphthyl) propylhydroxyphosphinyl] oxy] -2-phenylethanoic acid; 2- [[(2-naphthyl) propylhydroxyphosphinyl] oxy] -2-phenylethanoic acid; 2- [[(1-naphthyl) butylhydroxyphosphinyl] oxy] -2-phenylethanoic acid; 2- [[(2-naphthyl) butylhydroxyphosphinyl] oxy] -2-phenylethanoic acid; 2- [[Phenylprop-2-enylhydroxyphosphinyl] oxy] -2-phenylethanoic acid; 2- [(Methylhydroxyphosphinyl) oxy] hexanedioic acid; 2- [(Benzylhydroxyphosphinyl) oxy] hexanedioic acid; 2- [(Methylhydroxyphospholinyl) oxy] heptanedioic acid; 2- [(Benzylhydroxyphosphinyl) oxy] heptanedioic acid; 2- [(Methylhydroxyphosphinyl) oxy] octanedioic acid; 2- [(benzylhydroxyphosphinyl) oxy] octanedioic acid; 2- [(Methylhydroxyphosphinyl) oxy] nonanodioic acid; 2- [(benzylhydroxyphosphinyl) oxy] nonanodioic acid; 2- [(Methylhydroxyphosphinyl) oxy] decanedioic acid; 2- [(benzylhydroxyphosphinyl) oxy] decanedioic acid; 2- [[benzylhydroxyphosphinyl] oxy] -2-methyl-ethanoic acid; 2- [[benzylhydroxyphosphinyl] oxy] -2-ethyl-ethanoic acid; 2- [[benzylhydroxyphosphinyl] oxy] -2-propyl-ethanoic acid; 2- [[benzylhydroxyphosphinyl] oxy] -2-butyl-ethanoic acid; 2- [[benzylhydroxyphosphinyl] oxy] -2-cyclohexyl-ethanoic acid; 2- [[benzylhydroxyphosphinyl] oxy] -2- (cyclohexyl) methylethanoic acid; i 2- [[benzylhydroxyphosphinyl] oxy] -2-phenyl-ethanoic acid; 2- [[benzylhydroxyphosphinyl] oxy] -2-benzyl-ethanoic acid; 2- [[benzylhydroxyphosphinyl] oxy] -2-phenylethyl-ethanoic acid; 2- [[benzylhydroxyphosphinyl] oxy] -2-phenylpropyl-ethanoic acid; 2- [[benzylhydroxyphosphinyl] oxy] -2-phenylbutyl-ethanoic acid; 2- [[benzylhydroxyphosphinyl] oxy] -2- (2, 3, 4-trimethoxyphenyl) ethanoic acid; 2- [[benzylhydroxyphosphinyl] oxy] -2- (1-naphthyl) -ethanoic acid; 2- [[benzylhydroxyphosphinyl] oxy] -2- (2-naphthyl) -ethanoic acid; 2- [[benzylhydroxyphosphinyl] oxy] -2- (1-naphthyl) -methylethanoic acid; 2- [[benzylhydroxyphosphinyl] oxy] -2- (2-naphthyl) -methanolatanoic acid; 2- [benzylhydroxyphosphinyl] oxy] -2 ~ (l-naphthyl) -ethylethanoic acid; 2- [[benzylhydroxyphosphinyl] oxy] -2- (2-naphthyl) -ethylatanoic acid; 2- [[benzylhydroxyphosphinyl] oxy] -2- (1-naphthyl) -propylethanoic acid; 2- [[benzylhydroxyphosphinyl] oxy] -2- (2-naphthyl) -propylethanoic acid; 2- [[benzylhydroxyphosphinyl] oxy] -2- (1-naphthyl) -butylethanoic acid; 2- [[benzylhydroxyphosphinyl] oxy] -2- (2-naphthyl) -butylethanoic acid; 2- [[benzylhydroxyphosphinyl] oxy] -2-phenylprop-2-enylethanoic acid; 2- [[(2-pyridyl) methylhydroxyphosphinyl] oxy] -pentanedioic acid; 2- [[(3-pyridyl) methylhydroxyphosphinyl] oxy] -pentanedioic acid; 2- [[(4-pyridyl) methylhydroxyphosphinyl] oxy] -pentanedioic acid; 2- [[(3-pyridyl) ethylhydroxyphosphinyl] oxy] -pentanedioic acid; 2- [[(3-pyridyl) propylhydroxyphosphinyl] oxy] -pentanedioic acid; 2- [[(tetrahydrofuranyl) methylhydroxyphosphinyl] -oxy] pentanedioic acid; 2- [[(tetrahydrofuranyl) ethylhydroxyphosphinyl] -oxy] pentanedioic acid; 2- [[(tetrahydrofuranyl) propylhydroxy-phosphinyl] oxy] pentanedioic acid; 2- [[(2-indolyl) methylhydroxyphosphinyl] oxy] -pentanedioic acid; 2- [[(3-indolyl) methylhydroxyphosphinyl] oxy] -pentanedioic acid; 2- [[(4-indolyl) methylhydroxyphosphinyl] oxy] -pentanedioic acid; 2- [[(3-indolyl) ethylhydroxyphosphinyl] oxy] -pentanedioic acid; 2- [[(3-indolyl) propylhydroxyphosphinyl] oxy] - x pentanedioic acid; 2 - [[(2-thienyl) methylhydroxyphosphinyl] oxy] -pentanedioic acid; 2- [[(3-thienyl) methylhydroxyphosphinyl] oxy] -pentanedioic acid; 2- [[(4-thienyl) methylhydroxyphosphinyl] oxy] -pentanedioic acid 2 - [[(3-thienyl) ethylhydroxyphosphinyl] oxy] -pentanedioic acid; 2- [[(3-thienyl) propylhydroxyphosphinyl] oxy] -pentanedioic acid; and pharmaceutically acceptable salts and hydrates thereof. In another preferred embodiment of formula I, R 2 is selected from the group consisting of hydrogen, straight or branched chain C 1 -Cg alkyl, straight or branched chain C 2 -C 9 alkenyl, C 3 -C 8 cycloalkyl, cycloalkenyl C5-C7, benzyl and phenyl, wherein R2 is substituted or unsubstituted with one or more substituents independently selected from the group consisting of C3-C8 cycloalkyl, C5-C7 cycloalkenyl, straight chain C6-C6 alkyl or branched, straight or branched chain C2-C6 alkenyl, C? ~ C4 alkoxy, and phenyl. Exemplary compounds of this embodiment include: 2- [[(2-pyridyl) methylhydroxyphosphinyl] oxy] -2-phenylethanoic acid; 2- [[(3-pyridyl) methylhydroxyphosphinyl] oxy] -2-phenylethanoic acid; 2- [[(4-pyridyl) methylhydroxyphosphinyl] oxy] -2-phenylethanoic acid; 2- [[(3-pyridyl) ethylhydroxyphosphinyl] oxy] -2-phenylethanoic acid; 2- [[(3-pyridyl) propylhydroxyphosphinyl] oxy] -2-phenylethanoic acid; 2- [[(tetrahydrofuranyl) methylhydroxyphosphinyl] -oxy] -2-phenylethanoic acid; 2- [[(tetrahydrofuranyl) ethylhydroxyphosphinyl] -oxy] -2-phenylethanoic acid; 2- [[(tetrahydrofuranyl) propylhydroxy-phosphinyl] oxy] -2-phenylethanoic acid; 2- [[(2-indolyl) methylhydroxyphosphinyl] oxy] -2-phenylethanoic acid; 2- [[(3-indolyl) methylhydroxyphosphinyl] oxy] -2-phenylenoic acid; 2- [[(4-indolyl) methylhydroxyphosphinyl] oxy] -2-phenylethanoic acid 2- [[(3-indolyl) ethylhydroxyphosphinyl] oxy] -2-phenylethanoic acid; 2- [[(3-indolyl) propylhydroxyphosphinyl] oxy] -2- x phenylethanoic acid; 2 - [[(2-thienyl) methylhydroxyphosphinyl] oxy] -2-phenylethane! ce- 2 - [[(3-thienyl) methylhydroxyphosphinyl] oxy] -2-phenylethanoic acid; 2- [[(4-thienyl) methylhydroxyphosphinyl] oxy] -2-phenylethanoic acid; 2- [[(3-thienyl) ethylhydroxyphosphinyl] oxy] -2-phenylethanoic acid; 2- [[(3-thienyl) propylhydroxyphosphinyl] oxy] -2-phenylethanoic acid- 2- [[benzylhydroxyphosphinyl] oxy] -2- (2-pyridyl) -methyleneethaneice- 2- [[benzylhydroxyphosphinyl] oxy] -2 acid - (3-pyridyl) -methanoyanoic acid; 2- [[benzylhydroxyphosphinyl] oxy] -2- (4-pyridyl) -methanolatanoic acid; 2- [[benzylhydroxyphosphinyl] oxy] -2- (3-pyridyl) -ethylethanoic acid; 2- [[benzylhydroxyphosphinyl] oxy] -2- (3-pyridyl) -propylethanoic acid 2- [[benzylhydroxyphosphinyl] oxy] -2- (tetrahydrofuranyl) methylethanoic acid; 2- [[benzylhydroxyphosphinyl] oxy] -2- (tetrahydro-furanyl) ethylethanoic acid; 2- [[benzylhydroxyphosphinyl] oxy] -2- (tetrahydrofuranyl) propylethanoic acid; 2- [[benzylhydroxyphosphinyl] oxy] -2- (2-indolyl) methylethanoic acid; 2- [[benzylhydroxyphosphinyl] oxy] -2- (3-indolyl) -methanolatanoic acid; 2- [[benzylhydroxyphosphinyl] oxy] -2- (4-indolyl) -methanolamic acid; 2- [[benzylhydroxyphosphinyl] oxy] -2- (3-indolyl) -ethylethanoic acid; 2- [[benzylhydroxyphosphinyl] oxy] -2- (3-indolyl) -propylethanoic acid; 2- [[benzylhydroxyphosphinyl] oxy] -2- (2-thienyl) -methanolatanoic acid; 2- [[benzylhydroxyphosphinyl] oxy] -2- (3-thienyl) -methanolatanoic acid; 2- [[benzylhydroxyphosphinillaxy] -2- (4-thienyl) -methanolatanoic acid; 2- [benzylhydroxyphosphinyl] oxy] -2- (3-thienyl) -ethylethanoic acid; 2- [[benzylhydroxyphosphinyl] oxy] -2- (3-thienyl) propylethanoic acid; and pharmaceutically acceptable salts and hydrates thereof. When X is NR5, R2 is preferably substituted with carboxy.

Exemplary compounds of this embodiment include: 2- [[methylhydroxyphosphinyl] amino] pentanedioic acid; 2- [[ethylhydroxyphosphinyl] amino] pentanedioic acid; 2- [[propylhydroxyphosphinyl] amino] pentanedioic acid; 2- [[butylhydroxyphosphinyl] amino] pentanedioic acid; 2- [[cyclohexylhydrosxyphosphinyl] amino] pentanedioic acid; 2- [[(Cyclohexyl) methylhydroxyphosphinyl] amino] -pentanedioic acid; 2- [[phenylhydroxyphosphinyl] amino] pentanedioic acid; 2- [[benzylhydroxyphosphinyl] amino] pentanedioic acid; 2- [[phenylethylhydroxyphosphinyl] amino] pentanedioic acid; 2- [[Phenylpropylhydroxyphosphinyl] amino] pentanedioic acid; 2- [[phenylbutylhydroxyphosphinyl] amino] pentane-dioic acid; 2- [[(4-methylbenzyl) hydroxyphosphinyl] amino] -pentanedioic acid; 2- [[(4-fluorobenzyl) hydroxyphosphinyl] amino] -pentanedioic acid; 2- [[(2-fluorobenzyl) hydroxyphosphinyl] amino] -X-pentanedioic acid; 2- [[(pentafluorobenzyl) hydroxyphosphinyl] -amino] pentanedioic acid; 2- [[(methoxybenzyl) hydroxyphosphinyl] amino] -pentanedioic acid; 2- [[(2, 3, 4-trimethoxyphenyl) hydroxyphosphinyl] -amino] pentanedioic acid; 2- [[(1-naphthyl) hydroxyphosphinyl] amino] pentanedioic acid; 2- [[(2-naphthyl) hydroxyphosphinyl] amino] pentanedioic acid; 2- [[(1-naphthyl) methylhydroxyphosphinyl] amino] -pentanedioic acid; 2- [[(2-naphthyl) methylhydroxyphosphinyl] amino] -pentanedioic acid; 2 - [[(1-naphthyl) ethylhydroxyphosphinyl] amino] -pentanedioic acid; 2- [[(2-naphthyl) ethylhydroxyphosphinyl] amino] -pentanedioic acid; 2- [[(1-naphthyl) propylhydroxyphosphinyl] amino] -pentanedioic acid; 2 - [[(2-naphthyl) propylhydroxyphosphinyl] amino] -pentanedioic acid; 2- [[(1-naphthyl) butylhydroxyphosphinyl] amino] -pentanedioic acid; 2 - [[(2-naphthyl) butylhydroxyphosphinyl] amino] -pentanedioic acid; 2- [[(Phenylprop-2-enyl) hydroxyphosphinyl] amino] -pentanedioic acid; 2- [[benzylhydroxyphosphinyl] amino] pentanedioic acid; 2- [[(2-fluorobenzyl) hydroxyphosphinyl] amino] -2-pentanedioic acid; 2- [[((Hydroxy) phenylmethyl) hydroxyphosphinyl] -amino] pentanedioic acid; 2- [[(3-methylbenzyl) hydroxyphosphinyl] amino] -pentanedioic acid; 2- [[(4-fluorophenyl) hydroxyphosphinyl] amino] -pentanedioic acid; 2- [(phosphono) amino] pentanedioic acid; 2- [[(3-trifluoromethylbenzyl) hydroxyphosphinyl] -amino] pentanedioic acid; 2- [(Methylhydroxyphosphinyl) amino] hexanedioic acid; 2- [(benzylhydroxyphosphinyl) amino] hexanedioic acid; 2- [(Methylhydroxyphosphinyl) amino] heptanedioic acid; 2- [(benzylhydroxyphosphinyl) amino] heptanedioic acid; 2- [(Methylhydroxyphosphinyl) amino] octanedioic acid; 2- [(benzylhydroxyphosphinyl) amino] octanedioic acid; 2- [(Methylhydroxyphosphinyl) amino] nonanodioic acid; x 2- [(benzylhydroxyphosphinyl) amino] nonanodioic acid; 2- [(Methylhydroxyphosphinyl) amino] decanedioic acid; 2- [(benzylhydroxyphosphinyl) amino] decanedioic acid; 3- [[(2-pyridyl) methylhydroxyphosphinyl] amino] -pentanedioic acid; 3- [[(3-pyridyl) methylhydroxyphosphinyl] amino] -pentanedioic acid; 3- [[(4-pyridyl) methylhydroxyphosphinyl] amino] -pentanedioic acid; 3- [[(3-pyridyl) ethylhydroxyphosphinyl] amino] -pentanedioic acid; 3- [[(3-pyridyl) propylhydroxyphosphinyl] amino] -pentanedioic acid; 3- [[(tetrahydrofuranyl) methylhydroxyphosphinyl] -amino] pentanedioic acid; 3- [[(tetrahydrofuranyl) ethylhydroxyphosphinyl] -amino] entanedioic acid; 3- [[(Tetrahydrofuranyl) propylhydroxy-phosphinyl] amino] pentanedioic acid; 3- [[(2-indolyl) methylhydroxyphosphinyl] amino] -pentanedioic acid; 3- [[(3-indolyl) methylhydroxyphosphinyl] amino] -pentanedioic acid; 3- [[(4-indolyl) methylhydroxyphosphinyl] amino] -pentanedioic acid; 3- [[(3-indolyl) ethylhydroxyphosphinyl] amino] -pentanedioic acid; 3- [[(3-indolyl) propylhydroxyphosphinyl] amino] -pentanedioic acid; 3- [[(2-thienyl) methylhydroxyphosphinyl] amino] -pentanedioic acid; 3 - [[(3-thienyl) methylhydroxyphosphinyl] amino] -pentanedioic acid 3- [[(4-thienyl) methylhydroxyphosphinyl] amino] -pentanedioic acid; 3- [[(3-thienyl) ethylhydroxyphosphinyl] amino] -pentanedioic acid; 3- [[(3-thienyl) propylhydroxyphosphinyl] amino] -pentanedioic acid; and pharmaceutically acceptable salts and hydrates thereof. In another preferred embodiment, R 2 is selected from the group consisting of hydrogen, C 1 -Cg straight or branched chain alkyl, C 2 -Cg straight or branched chain alkenyl, C 3 -Cg cycloalkyl, C 5 -C 7 cycloalkenyl, benzyl and phenyl, wherein R2 is substituted or unsubstituted with one or more substituents independently selected from the group consisting of C3-C8 cycloalkyl, C5-C7 cycloalkenyl, straight or branched chain Ci-C3 alkyl, C2- alkenyl C6 straight or branched chain, C? -C4 alkoxy, and phenyl.

Exemplary compounds of this embodiment include: 2- [[methylhydroxyphosphinyl] amino] -2-phenyl-ethanoic acid; 2- [[ethylhydroxyphosphinyl] amino] -2-phenyl-ethanoic acid; 2- [[propylhydroxyphosphinyl] amino] -2-phenyl-ethanoic acid; 2- [[butylhydroxyphosphinyl] amino] -2-phenyl-ethanoic acid; 2- [[cyclohexylhydroxyphosphinyl] amino] -2-phenylethanoic acid; 2- [[(cyclohexyl) methylhydroxyphosphinyl] amino] -2-phenylethanoic acid; 2- [[phenylhydroxyphosphinyl] amino] -2-phenylethanoic acid; 2- [[benzylhydroxyphosphinyl] amino] -2-phenyl-ethanoic acid; 2- [[phenylethylhydroxyphosphinyl] amino] -2-phenyl-ethanoic acid; 2- [[Phenylpropylhydroxyphosphinyl] amino] -2-phenylethanoic acid 2- [[phenylbutylhydroxyphosphinyl] amino] -2-phenylethanoic acid; 2- [[(2,3-trimethoxyphenyl) -3-hydroxy-X-phosphinyl] amino] -2-phenylethanoic acid; 2- [[(1-naphthyl) hydroxyphosphinyl] amino] -2-phenyl-ethanoic acid; 2- [[(2-naphthyl) hydroxyphosphinyl] amino] -2-phenylethanoic acid; 2- [[(1-naph il) methylhydroxyphosphinyl] amino] -2-phenylethanoic acid 2- [[(2-naphthyl) methylhydroxyphosphinyl] amino] -2-phenylethanoic acid 2- [[(1-naphthyl) ethylhydroxyphosphinyl] acid ] amino] -2-phenylethanoic; 2- [[(2-naphthyl) ethylhydroxyphosphinyl] amino] -2-phenylethanoic acid; 2 - [[(naphthyl) propylhydroxyphosphinyl] amino] -2-phenylethanoic acid; 2- [[(2-naphthyl) propylhydroxyphosphinyl] amino] -2-phenylethanoic acid; 2 - [[(naphthyl) butylhydroxyphosphinyl] amino] -2-phenylethanoic acid; 2- [[(2-naphthyl) butylhydroxyphosphinyl] amino] -2-phenylethanoic acid 2- [[phenylprop-2-enylhydroxyphosphinyl] amino] -2-phenylethanoic acid; 2- [[benzylhydroxyphosphinyl] amino] -2-methyl-ethanoic acid; 2- [[benzylhydroxyphosphinyl] amino] -2-ethyl-ethanoic acid acid; 2- [[benzylhydroxyphosphinyl] amino] -2-propyl-ethanoic acid; 2- [[benzylhydroxyphosphinyl] amino] -2-butyl-ethanoic acid; 2- [[benzylhydroxyphosphinyl] amino] -2-cyclohexylethanoic acid; 2- [[benzylhydroxyphosphinyl] amino] -2- (cyclohexyl) methylethanoic acid; 2- [[benzylhydroxyphosphinyl] amino] -2-phenyl-ethanoic acid; 2- [[benzylhydroxyphosphinyl] amino] -2-benzyl-ethanoic acid; 2- [[benzylhydroxyphosphinyl] amino] -2-phenylethyl-ethanoic acid; 2- [[benzylhydroxyphosphinyl] amino] -2-phenylpropylatanoic acid; 2- [[benzylhydroxyphosphinyl] amino] -2-phenyl-butylethanoic acid; 2- [[benzylhydroxyphosphinyl] amino] -2- (2,3-trimethoxyphenyl) ethanoic acid; 2- [[benzylhydroxyphosphinyl] amino] -2- (1-naphthyl) ethanoic acid; 2- [[benzylhydroxyphosphinyl] amino] -2- (2- x naphthyl) ethanoic acid; 2- [[benzylhydroxyphosphinyl] amino] -2-finyl-ethyl) -ethylethanoic acid; 2- [[benzylhydroxyphosphinyl] amino] -2- (2-naphthyl) methylethanoic acid; 2- [[benzylhydroxyphosphinyl] amino] -2- (1-naphthyl) ethylethanoic acid; 2- [[benzylhydroxyphosphinyl] amino] -2- (2-naphthyl) ethylethanoic acid; 2- [[benzylhydroxyphosphinyl] amino] -2- (1-naphthyl) propylethanoic acid; 2- [[benzylhydroxyphosphinyl] amino] -2- (2-naphthyl) propylethanoic acid; 2- [[benzylhydroxyphosphinyl] amino] -2- (1-naphthyl) butytanoic acid; 2- [[benzylhydroxyphosphinyl] amino] -2- (2-naphthyl) butynatanoic acid; 2- [[benzylhydroxyphosphinyl] amino] -2-phenolprop-2-enylethanoic acid; 2- [[(2-pyridyl) methylhydroxyphosphinyl] amino] -2-phenylethanoic acid 2- [[(3-pyridyl) methylhydroxyphosphinyl] amino] -2-phenylethanoic acid; 2- [[(4-pyridyl) methylhydroxyphosphinyl] amino] -2-phenylethanoic acid; 2- [[(3-pyridyl) ethylhydroxyphosphinyl] amino] -2-phenylethanoic acid 2- [[(3-pyridyl) propylhydroxyphosphinyl] amino] -2-phenylethanoic acid; 2- [[(tetrahydrofuranyl) methylhydroxyphosphinyl] -amino] -2-phenylethanoic acid; 2- [[(tetrahydrofuranyl) ethylhydroxyphosphinyl] -amino] -2-phenylethanoic acid; 2- [[(tetrahydrofuranyl) propylhydroxy-phosphinyl] amino] -2-phenylethanoic acid; 2- [[(2-indolyl) methylhydroxyphosphinyl] amino] -2-phenylethanoic acid; 2- [[(3-indolyl) methylhydroxyphosphinyl] amino] -2-phenylethanoic acid; 2- [[(4-indolyl) methylhydroxyphosphinyl] amino] -2-phenylethanoic acid 2- [[(3-indolyl) ethylhydroxyphosphinyl] amino] -2-phenylethanoic acid; 2- [[(3-indolyl) propylkydroxyphosphinyl] amino] -2-phenylethanoic acid; 2- [[(2-thienyl) methylhydroxyphosphinyl] amino] -2-phenylethanoic acid 2- [[(3-thienyl) methylhydroxyphosphinyl] amino] -2-phenylethanoic acid; 2- [[(4-thienyl) methylhydroxyphosphinyl] amino] -2- X-phenylethanoic acid 2- [[(3-thienyl) ethylhydroxyphosphinyl] amino] -2-phenylethanoic acid; 2- [[(3-thienyl) propylhydroxyphosphinyl] amino] -2-phenylethanoic acid; 2- [[benzylhydroxyphosphinyl] amino] -2- (2-pyridyl) methylethanoic acid; 2- [[benzylhydroxyphosphinyl] amino] -2- (3-pyridyl) methylethanoic acid; , 2- [[benzylhydroxyphosphinyl] amino] -2- (4-pyridyl) methylethanoic acid; 2- [[benzylhydroxyphosphinyl] amino] -2- (3-pyridyl) ethylethanoic acid; 2- [[benzylhydroxyphosphinyl] amino] -2- (3-pyridyl) propylethanoic acid; 2- [[benzylhydroxyphosphinyl] amino] -2- (tetrahydrofuranyl) methylethanoic acid; 2- [[benzylhydroxyphosphinyl] amino] -2- (tetrahydrofuranyl) ethylethanoic acid; 2- [[benzylhydroxyphosphinyl] amino] -2- (tetrahydrofuranyl) propylethanoic acid; 2- [[benzylhydroxyphosphinyl] amino] -2- (2-indolyl) methylethanoic acid; 2- [[benzylhydroxyphosphinyl] amino] -2- (3-indolyl) methylethanoic acid; 2- [[benzylhydroxyphosphinyl] amino] -2- (2-indolyl) methylethanoic acid; 2- [[benzylhydroxyphosphinyl] amino] -2- (3-indolyl) ethylethanoic acid; 2- [[benzylhydroxyphosphinyl] amino] -2- (3-indolyl) propylethanoic acid; 2- [[benzylhydroxyphosphinyl] amino] -2- (2-thienyl) methylethanoic acid; 2- [[benzylhydroxyphosphinyl] amino] -2- (3-thienyl) methylethanoic acid; 2- [[benzylhydroxyphosphinyl] amino] -2- (4-thienyl) methylethanoic acid; 2- [[benzylhydroxyphosphinyl] amino] -2- (3-thienyl) ethylethanoic acid; 2- [[benzylhydroxyphosphinyl] amino] -2- (3-thienyl) -rypiletanoic acid; and pharmaceutically acceptable salts and hydrates thereof. Synthesis of NAALADase Inhibitors The NAALADase inhibitors of formula I can be prepared rapidly by standard techniques of organic chemistry, using the general synthetic trajectories described in the following in Schemes I-IX. The precursor compounds can be prepared by methods known in the art, such as those described by X 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 I HCl, Reflux Methods for substituting the R group are known in the art. Additional methods of synthesizing phosphinic acid esters are described in J. Med. Chem. , Vol. 31, pp. 204-212 (1988), and set forth in the following in Scheme II.

Scheme II Method A EtOH 0 II R -P - H OH A. R '= n (CH2) 3Ph H. R' = n-C7H15 B. (CH2) 4Ph I. n-C8H17 C. (CH2) 5Ph J. n- C9H19 D. (CH2) 4 (PF-Ph ) K. CH2CHCH3C4H9 E. (CH2) 4- (3-pyridyl) L. CH2 (CH3) C (CH3) 2 F. n-C5H ?? G. n-C6H? 3 Method B N. R '= n-C4H9 O. CHCH3C5Hu Starting with the aforementioned phosphinic acid ester, there are a variety of routes for preparing the compounds of formula I. For example, a general route has been described in J. Med. Chem. ., Vol. 39, pp. 619-622 (1996), and is set forth in the following in Scheme III. Scheme lll Other routes for preparing the compounds of formula I are set forth in Scheme IV and Scheme V below. Scheme IV and Scheme V show the starting material as an acid derivative phosphinics and the R group as any reasonable chemical substituent that it includes, without limitation, the substituents listed in Scheme II and throughout the specification. Another route to prepare the compounds of Scheme IV Formula I takes into account the aromatic substitution in Ri, and is established in the following in Scheme VI.

Scheme VI Another route to prepare the compounds of the formula I taking into account the aromatic substitution in the R2 position, and is established in the following in Scheme VII.

VH scheme KOH (ac) EtOH BnBr K2C03 Another route for preparing the compounds of formula I wherein X is NR5 is set forth in the following in Scheme VIII. Another route to prepare the compounds of Scheme VIII Formula I wherein X is oxygen is set forth in the following in Scheme IX.

Scheme IX PREFERRED PROFARMATES The prodrugs of the present invention are designed to overcome any pharmacokinetic or pharmaceutical problems that prevent the optimal use of NAALADase inhibitors. In particular, prodrugs are formulated with the objectives of improving chemical stability, improving patient acceptance and complacency, improving bioavailability, prolonged duration of action, improving organic selectivity, improving formulation (eg, increased water solubility), and / or reduced side effects (eg, toxicity). The majority of the prodrugs of the present invention do not possess any relevant pharmacological activity. As such, it is important that the prodrugs completely convert the active portions in vivo because an intact prodrug represents an unavailable drug. The conversion or activation of prodrugs in the body can occur by various chemical or enzymatic reactions. For example, reductive and oxidative reactions can be used to regenerate the active portion in vivo. However, most prodrugs require a hydrolytic cleavage mediated by enzymatic catalysis to activate the release of the active portion. Enzymes present in the wall of the intestine, liver, and blood are important in metabolizing the prodrugs. Due to the wide variety of esterases present in target tissues for the regeneration of oral prodrugs, esters are the most common prodrugs when considering gastrointestinal absorption. For the appropriate esterification of molecules containing hydroxyl or carboxyl groups, it is possible to obtain derivatives with at least some desirable hydro- or lipophilicity as well as lability in vivo. Based on the above considerations, a preferred prodrug of the present invention is a compound of formula II or a pharmaceutically acceptable salt or hydrate thereof, wherein: X is CR5R6 / NR7 or 0; Ri and R7 are independently selected from the group consisting of hydrogen, straight or branched chain C1-C9 alkyl, straight or branched chain C2-Cg alkenyl, C3-Cs cycloalkyl, C5-C7 cycloalkenyl and Ar , wherein Ri and R7 are independently unsubstituted or substituted with one or more substituents independently selected from the group consisting of carboxy, C3-Ca cycloalkyl, Cs-C7 cycloalkenyl, halo, hydroxy, nitro, trifluoromethyl, C? -C0 straight or branched chain, C2-Ce alkenyl straight or branched chain, C? -Cg alkoxy, C2-Cg alkenyloxy, phenoxy, benzyloxy, amino, and Ar2; R2 is selected from the group consisting of hydrogen, straight or branched chain C1-C9 alkyl, straight or branched chain C2-Cg alkenyl, C3-C8 cycloalkyl / C5-C7 cycloalkenyl and Ari, wherein such R2 is substituted or unsubstituted with one or more substituents independently selected from the group consisting of carboxy, C3-Cs cycloalkyl, C5-C7 cycloalkenyl, halo, hydroxy, nitro, trifluoromethyl, straight or branched chain C6-6 alkyl , straight or branched chain C2-C6 alkenyl, C6-C6 alkoxy, C2-C6 alkenyloxy, phenoxy, benzyloxy, amino, and Ar2; R3 and R are independently selected from the group consisting of hydrogen, carboxy, straight or branched chain C1-C9 alkyl, straight or branched chain C2-C9 alkenyl, C3-C8 cycloalkyl, C5-C7 cycloalkenyl, and Ari, with the proviso that both of R3 and R4 are not hydrogen; wherein R3 and R4 are independently unsubstituted or substituted with one or more substituents independently selected from the group consisting of carboxy, C3-C3 cycloalkyl, C5-C7 cycloalkenyl, halo, hydroxy, nitro, trifluoromethyl, C? C6 straight or branched chain, straight or branched chain C2-Ce alkenyl, C6-6 alkoxy, C2-C6 alkenyloxy, phenoxy, benzyloxy, amino, and Ar2; R $ and Re are independently selected from the group consisting of hydrogen, straight or branched chain C-Qβ alkyl, straight or branched chain C2-C6 alkenyl, C3-C8 cycloalkyl, C5-C7 cycloalkenyl, Ar1 ( and halo, Ri and Ar2 are independently 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 Ari and Ar2 are independently unsubstituted or substituted with one or more substituents independently selected from the group consisting of halo, hydroxy, nitro, trifluoromethyl , straight or branched chain Ci-Cß alkyl, straight or branched chain C 2 -C alkenyl, C?-C 6 alkoxy, C 2 -C 6 alkenyloxy, phenoxy, benzyloxy, and amino In a preferred embodiment, R 4 is hydrogen, and R is substituted with one or more independently selected substituents of the group consisting of carboxy, Ci-Cβ alkoxy, C2-Cd alkenyloxy, phenoxy, and benzyloxy. In the most preferred embodiment, the prodrug is selected from the group consisting of: 2- [(benzylmethoxyphosphinyl) methyl] pentanedioic acid; 2- [(benzyl-ethoxy-phosphinyl) methyl] pentandioic acid; 2- [(benzylpropoxyphosphinyl) methyl] pentandioic acid; 2- [(benzylacetoxyphosphinyl) methyl] pentanedioic acid; 2- [(benzylbenzyloxyphosphinyl) methyl] pentandioic acid; 2- [(benzyl (1-oxopropoxy) methoxyphosphonoyl) methyl] pentanedioic acid; 2- [(pentafluorobenzylmethoxyphosphyl) methyl] pentandioic acid; 2- [(pentafluorobenzyletoxyphosphyl) methyl] pentandioic acid; 2- [(pentafluorobenzylpropoxyphosphinyl) methyl] pentandioic acid; 2- [(pentafluorobenzylacetoxyphosphinyl) methyl] pentandioic acid 2- [(pentafluorobenzyl (1-oxo-propoxy) phosphinyl) methyl] -pentanedioic acid; and pharmaceutically acceptable salts and hydrates thereof. The compounds of the present invention possess one or more asymmetric centers and thus can be produced as mixtures (racemic and non-racemic) of stereoisomers, or as individual R- and S-stereoisomers. The individual stereoisomers can be obtained using an optically active starting material, determining a racemic or non-racemic mixture of an intermediate at some appropriate stage of synthesis, or determining a compound of the formula I. Synthesis of Prodrugs A general route for preparing the prodrugs of Formula II is set forth in the following in Scheme X.

Scheme X Other prodrugs can be readily prepared from the above-mentioned NAALADase inhibitors using methods known in the art, such as those described by Burger's Medicinal Chemists try and Drug Chemists, Fifth Ed., Vol. 1, p. 172-178, 949-982 (1995). For example, NAALADase inhibitors containing an alcoholic or phenolic group (R-OH) can be conveniently modified to the following labile esters or ethers: • Simple or functionalized aliphatic carboxylic esters or acids: R-O-CO-R '. • Esters of carbamic acids: RO-CO-NR 'R. "• Esters of amino acids (eg, lysine): RO-CO- CH (NH2) R'. • Substituted ring aromatic esters: RO-CO- aryl • Derivatized phosphoric acid esters: RO-PO (OR ') (OR "). • Esters of (acyloxy) methyl or of (acyloxy) ethyl: R-0-CH2-0-CO-R 'or R-0-CH (CH3) -O-CO-R'. • Esters of (Alkoxycarbonyloxy) methyl or alkoxycarbonyloxy) ethyl: R-0-CH2-0-CO-0-R 'or R-O-CH (CH3) -0- CO-O-R'. • O-glycosides. NAALADase inhibitors containing a carboxylic group (R-COOH) can form esters and amides. Numerous studies have documented their structure-metabolism relationship. Prodrugs of carboxylic acids include the following: • Esters of simple alcohols or phenols: R-CO-O-R '. • Esters of alcohols containing an amino or amido function: R-CO-O- (CH2) n NR'R ", R-CO-0- (CH2) n-CO-NR 'R" or R-CO-0 - (CH2) n-NH-COR '.

• Esters of (acyloxy) methyl or of (acyloxy) ethyl: R-CO-0-CH 2 -O-CO-R 'or R-CO-0-CH (CH 3) -O-CO-R'. • Hybrid glycerides formed from diacylglycerols: R-CO-0-CH (CH2-0-CO-R ') 2. • Esters of diacylaminopropan-2-oles: R-CO-0-CH (CH2-NH-COR ') 2 • Derivatives of N / -Dialkylhydroxylamine: R-CO-0-? R'R "• Amides of amino acids (eg, glycine): R-CO-? H- CH (R ') -COOH. AALADase containing a group? H (RR '? - H, ie, amides, imides, and amines) are treatable for modification to a variety of prodrugs: • Amides formed from simple or functionalized acyl groups: RR'? - CO-R. " • Amides divided by intramolecular catalysis (with cyclization accompanied by the carrier portion). ® Alkyl carbamates: RR '? -CO-OR. "• (Acyloxy) alkylcarbamates: RR'? -CO-O-CH (R") -O-CO-R "'. • (Phosphoryloxy) methylcarbamates: RR' ? -CO-0-CH2-0-P03H2 • Derivatives of N- (Acyloxy) methyl or N- (acylaxy) ethyl: RR '? - CH2-O-CO-R "or RR'? - CH (CH3) -O-CO-R. "• N-Mannich Bases: RR '? -CH2-? R" R "' • N- (N, N-Dialkylamino) methylene derivative of primary amines: R? = CH-? R 'R'. • N-a-Hydroxyalkyl derivatives of peptides. β Imidazolidinone derivative of peptides.

• Oxazolidines of ephedrines and other l-hydroxy-2-aminoethane congeners. PHARMACEUTICAL COMPOSITIONS OF THE PRESENT INVENTION The present invention also relates to a pharmaceutical composition comprising: (i) an effective amount of a prodrug of a NAALADase inhibitor; and (ii) a pharmaceutically acceptable carrier. Examples of NAALADase inhibitors and prodrugs are as set forth in the foregoing. In preferred pharmaceutical compositions, the prodrug is present in an amount that is effective to treat an abnormality of glutamate, effect neuronal activity, treat a compulsive disorder, or treat a disease of the prostate in an animal. METHODS OF THE PRESENT INVENTION METHOD FOR TREATING GLUTAMATE ABNORMALITY While not limited to a single theory, it is believed that the NAALADase inhibitors used in the methods of the present invention modulate glutamate levels by acting in a glutamate storage form which it is hypothesized to be upstream of the effects mediated by the NMDA receptor. Therefore, the present invention also relates to a method for treating an abnormality of glutamate in an animal, which comprises administering an effective amount of a prodrug of a NAALADase inhibitor to such an animal. The glutamate abnormality can be any disease, disorder or condition in which glutamate is involved, including pathological conditions involving high levels of glutamate. Examples of glutamate abnormalities include without limitation epilepsy, stroke, Alzheimer's disease, Parkinson's disease, Amyotrophic Lateral Sclerosis (ALS), Huntington's disease, schizophrenia, chronic pain, ischemia, peripheral neuropathy, traumatic brain injury and physical damage to the spinal cord. In a preferred embodiment, the glutamate abnormality is selected from the group consisting of ischemia, stroke, Parkinson's disease, Amyotrophic Lateral Sclerosis (ALS) and spinal cord injury. METHOD FOR DEALING WITH COMPULSIVE DISORDER The inventors have unexpectedly found that NAALADase inhibitors are effective in treating compulsive disorders related to glutamate. Therefore, the present invention also relates to a method for treating a compulsive disorder, which comprises administering an effective amount of a prodrug of a NAALADase inhibitor to a patient in need thereof.

Compulsive disorder can 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 Touretter syndrome. - Preferably, compulsive disorder is a drug dependence. The commonly used drugs with potential for dependence include depressed CNS (opioids, synthetic narcotics, barbiturates, glutethimide, metiprilon, etclorvinol, methaqualone, alcohol); anxiolytics (diazepam, chlordiazepoxide, alprazolam, oxazepam, temazepam); stimulants (amphetamine, methamphetamine, cocaine); and hallucinogens (LSD, mescaline, peyote, marijuana). __ More preferably, the drug dependence is alcohol, nicotine, heroin or cocaine dependence. METHOD FOR PERFORMING NEURAL ACTIVITY It has been discovered that the inhibition of NAALADase promotes nerve regeneration and myelin formation. Therefore, the present invention further relates to a method for effecting neuronal activity in an animal, which comprises administering an effective amount of a prodrug of a NAALADase inhibitor to such an animal. The neuronal activity that is carried out by the method of the present invention can 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 a neurological disorder that is treatable by the method of the present invention include without limitation: trigeminal neuralgia; glossofaringeal neuralgia; Bell's palsy; myasthenia gravis; muscular dystrophy; Amyotrophic Lateral Sclerosis; progressive muscular atrophy; Progressive bulbar inherited muscular atrophy; invertebrate herniated, broth or fractured disc syndromes, cervical spondylosis; plexus disorders; syndromes of thoracic outlet destruction; peripheral neuropathies such as those caused by lead, dapsone, tics, porphyria, or Guillain-Barré syndrome; Alzheimer disease; and Parkinson's disease. The method of the present invention 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 that are related to neurodegeneration. Examples of demyelinating diseases include multiple sclerosis. Examples of neurological disorders that are related to neurodegeneration include Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis (ALS).

METHOD FOR TREATING PROSTATE DISEASE Additionally, the present invention relates to a method for treating a disease of the prostate in an animal, which comprises administering an effective amount of a prodrug of a NAALADase inhibitor to such an animal. In a preferred embodiment, the prostate disease is cancer of the prostate or benign prostatic hyperplasia. METHOD OF TREATING CANCER In addition to prostate cancer, other forms of cancer that can be treated with the compounds of the present invention include without limitation: tumors that produce ACTH, acute lymphocytic leukemia, acute non-lymphocytic leukemia, cancer of the adrenal cortex, cancer in the bladder, brain cancer, breast cancer, cancer of the cervix, chronic lymphocytic leukemia, chronic myelocytic leukemia, colorectal cancer, cutaneous T-cell lymphoma, endometrial cancer, esophageal cancer, Ewing sarcoma, gallbladder cancer, leukemia hairy cell, head and neck cancer, Hodgkin's lymphoma, Kaposi's sarcoma, kidney cancer, liver cancer, lung cancer (small and / or small cell), malignant peritoneal effusion, malignant pleural effusion, melanoma, mesothelioma, multiple myeloma, neuroblastoma, non-Hodgkin's lymphoma, osteosarcoma, ovarian cancer, ovarian cancer (germ cell), pancreatic cancer, cancer of the penis, retinoblastoma, skin cancer, soft tissue sarcoma, carcinomas of scaly cell, cancer _B? stomach, testicular cancer, thyroid cancer, trophoblastic neoplasms, cancer of the uterus, vaginal cancer, cancer of the vulva and ilm tumor. The compounds of the present invention are particularly useful in treating cancer of tissues where the enzymes of NAALADas reside. Such tissues include the prostate as well as the brain, kidney and testicles. ROUTE OF ADMINISTRATION In the methods of the present invention, the compounds may be administered orally, parenterally, by spray inhalation, topically, rectally, nasally, buccally, vaginally or via an implanted reservoir in dosage formulations containing carriers, adjuvants and vehicles. conventional non-toxic pharmaceutically acceptable. The term "parenteral" as used herein includes injection and subcutaneous, intravenous, intramuscular, intraperitoneal, intrathecal, intraventricular, intrasternal or intracranial infusion techniques. Invasive techniques are preferred, particularly direct administration to damaged neuronal tissue. To be therapeutically effective as central nervous system targets, the NAALADase inhibitors used in the methods of the present invention should readily penetrate the blood-brain barrier when administered peripherally. Compounds that can not penetrate the brain-blood 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 appropriate dispersants or humidifying agents and suspending agents. Sterile injectable preparations can also be sterile injectable solutions or suspensions in pharmaceutically acceptable non-toxic diluents or solvents, for example, as solutions in 1,3-butanediol. Among the vehicles and acceptable solvents that can be used are water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile fixed oils are conventionally employed as solvents or suspension media. For this purpose, any soft fixed oil such as a synthetic mono- or di-glyceride can 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. Additionally, the compounds can be administered orally in the form of capsules, tablets, suspensions or aqueous solutions. The tablets may contain carriers such as lactose and corn starch, and / or lubricating agents such as magnesium stearate. The capsules may contain diluents including lactose and dried corn starch. The aqueous suspensions may contain emulsifying and suspending agents combined with the active ingredient. Oral dosage forms may also contain sweeteners and / or flavorings and / or coloring agents. The compounds can also 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 so that they will melt in the rectum to release the drug. Such excipients include cocoa butter, beeswax and polyethylene glycols.

In addition, the compounds can be administered topically, especially when the conditions directed by the treatment involve readily accessible areas or organs for topical application, including neurological disorders of the eye, skin or lower intestinal tract. For topical application to the eye, or ophthalmic use, the compounds may be formulated as suspensions of the isotonic micronized, adjusted pH of the sterile saline solution or, preferably, as an isotonic solution, pH adjusted to the sterile saline solution, or or without a condom such as benzyl-alkyllium chloride. Alternatively, the compounds can be formulated in the ointments, such as petrolatum. For topical application to the skin, the compounds may be formulated into suitable ointments containing the suspended or dissolved compounds in, for example, mixtures with one or more of the following: mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene-compound polyoxypropylene, emulsified wax and water. Alternatively, the compounds may be formulated in 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 made in rectal suppository formulations (see above) or in suitable enema formulations. The NAALADase inhibitors used in the methods of the present invention can 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 adjusted to continuous infusion. Pumping means, particularly subcutaneous pumping means, are preferred for continuous infusion. DOSAGE Dosage levels in the order of about 0.1 mg to about 10,000 mg of the compound of the active ingredient are useful in the treatment of the above conditions, with preferred levels being from about 0.1 mg to about 1,000 mg. The specific dose level for any particular patient varies and depends on 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; the combination of the drug; the severity of the particular disease being treated; and the form of administration. Typically, the results of dosing effects in vi tro provide a useful guide on the appropriate doses for administration to the patient. Studies in animal models are also useful. Considerations for determining appropriate dose levels are well known in the art. In a preferred embodiment, the NAALADase inhibitors are administered in lyophilized form. In this case, 1 to 100 mg of a NAALADase inhibitor can be lyophilized in individual bottles, together with a carrier and a buffer, such as mannitol and sodium phosphate. The compound can be reconstituted in the bottles with bacteriostatic water before administration. Treating global ischemia, the compounds of the present invention are preferably administered, orally, rectally, parenterally or topically at least 1 to 6 times daily, and may follow an initial bolus dose of higher concentration. The NAALADase inhibitors used in the methods of the present invention can be administered in combination with one or more therapeutic agents, including chemotherapeutic agents. TABLE I provides known mean dosages for the selected chemotherapeutic agents. The specific dose levels for these agents and other therapeutic agents will depend on considerations such as those identified above for the compounds of the present invention. TABLE I ADMINISTRATION REGIME For the methods of the present invention, any administration regimen that regulates timing and drug delivery sequence may be used and may be repeated as a requirement for treatment. Such a regimen may include pretreatment and / or co-administration with additional therapeutic agents. To maximize nerve tissue protection from nerve attack, NAALADase inhibitors should be administered to affected cells as soon as possible. In situations where nervous attack is anticipated, the compounds should be administered before the expected nervous attack. Such situations of increased probability of nervous attack include surgery (cartoid, cardiac, vascular, aortic, orthopedic endarterectomy); endovascular procedures such as arterial catheterization (carotid, vertebral, aortic, cardia, renal, spinal, Adamkie icz); injections of embolic agents; spools or balloons for -mosmosis; vascularity interruptions for treatment of brain injuries; and predisposition of medical conditions such as passenger ischemic attacks. Where pretreatment for stroke or ischemia is impossible or impractical, it is important that NAALADase inhibitors reach the affected cells as soon as possible during or after the event. In the time period between strokes, diagnoses and treatment procedures should be minimized to save the cells from further damage and death.

For patients with prostate cancer that is neither advanced nor metastatic, the compounds of the present invention can be administered (i) prior to surgery or radiation treatment to reduce the risk of metastasis; (ii) during surgery or in conjunction with radiation treatment; and / or (iii) after surgery or radiation therapy to reduce the risk of recurrence and inhibit the growth of any residual tumor cells. For patients with advanced or metastatic prostate cancer, the compounds of the present invention can be administered as a continuous supplement to, or as a replacement for, hormonal ablation to retard tumor cell growth in both the untreated primary tumor and the lesions. existing metastatic The methods of the present invention are particularly useful where stripped cells could not be removed by surgical intervention. After post-surgical recovery, the methods of the present invention would be effective in reducing the chances of tumor recurrence engendered by such stripped cells. COMBINATION WITH OTHER TREATMENTS a. Nervous Attack In methods for treating nerve attack (particularly stroke of acute ischemia and global ischemia caused by head trauma or by flooding), 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 that can reduce the risk of a second case of ischemia (such as ticlopidine). The NAALADase inhibitors can be coadministered 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 agents, emulsifiers and Ph-buffers. b. Prostate Disease (i) Surgery and Radiation Treatment In general, surgery and radiation treatment are used as potentially curative therapies for patients with cancer located in the prostate who are under 70 years of age and are expected to live At least 10 more. Approximately 70% of patients with prostate cancer diagnosed recently fall into this category. Approximately 90% of these patients (65% of total patients) undergo surgery, while approximately 10% of these patients (7% of total patients) undergo radiation. The Histopathological examination of surgical specimens reveals that approximately 63% of patients who undergo surgery (40% of total patients) have locally extensive tumors or regional metastasis (lymph node) that was not detected at the initial diagnosis. These patients are at a significantly higher risk of recurrence. Approximately 40% of these patients will actually develop the recurrence within five years after the surgery. The results after radiation treatment are even less encouraging. Approximately 80% of patients who have undergone radiation treatment as their primary therapy have persistent disease or develop recurrence or metastasis within five years after treatment. Currently, most patients with prostate cancer who undergo surgery and radiation treatment do not receive any immediate therapy that repeats the therapy. Rather, they are frequently monitored by elevated Prostate Specific Antigen ("PSA"), which is the primary indicator of recurrence or metastasis. Based on the above statistics, there is considerable opportunity to use the present invention in conjunction with surgery and / or radiation treatment. (ii) Hormone Therapy Hormone ablation is the most effective palliative treatment for 10% of patients with metastatic prostate cancer. Hormone ablation by medication and / or orchiectomy is used to block hormones that promote the further growth and metastasis of cancer in the prostate. Over time, both the first and the metastatic tumors of virtually all these patients will become hormone independent and resistant to therapy. Approximately 50% of patients with metastatic cancer will die within three years after the initial diagnosis, and 75% of such patients will die within five years after diagnosis. Continuous supplementation with the compounds of the present invention can be used to prevent or reverse this permissive state of potentially metastasis. (iii) Chemotherapy While chemotherapy has been successful in treating some forms of cancer, it has shown mild therapeutic value by treating cancer in the prostate where it is usually reserved as a last resort. Therefore, the opportunity to treat cancer in the prostate by combining chemotherapy with the methods of the present invention will be rare. When combined, however, such treatments must be more effective than chemotherapy alone in controlling cancer in the prostate. (iv) Immunotherapy The compounds of the present invention can also be used in combination with monoclonal antibodies to treat cancer in the prostate. Such a combination treatment is particularly effective for patients with pelvic lymph node involvement, of which only 34% survive after 5 years. An example of such monoclonal antibodies is the specific membrane cell antiprostatic antibody. The present invention can also be used with immunotherapies based on polyclonal or monoclonal reagents of antibody derived. Derivative antibody monoclonal reagents are preferred. These reagents are well known in the art, and include radiolabelled monoclonal antibodies such as monoclonal antibodies conjugated with strontium-89. (v) Cryotherapy The methods of the present invention can also be used in conjunction with cryotherapy for the treatment of cancer in the prostate. In Vivo Toxicity of NAALADase Inhibitors To examine the toxicological effect of NAALADase inhibition in vivo, one group of mice was injected with 2- (phosphonomethyl) pentanedioic acid, a high activity NAALADase inhibitor, at doses of 1, 5, 10 , 30, 100, 300 and 500 mg / kg of body weight. Mice were subsequently observed twice a day for 5 consecutive days. The survival ratio at each dose level is given in the following in TABLE I. The results show that the NAALADase inhibitor is not toxic to mice, suggesting that it could be similarly non-toxic to humans when administered at therapeutically effective amounts. TABLE I In Vitro Inhibition of NAALADase Activity Several compounds of formula I were tested for inhibition of NAALADase activity. The results are provided in the following in the ILI Table.

TABLE II IN VITRO INHIBITION OF NAALADASA ACTIVITY Compound (Nm) 2- (phosphonomethyl) pentanedioic acid 2- (phosphonomethyl) succinic acid 2 - [[(2-carboxyethyl) hydroxyphosphonyl] -methyl] pentanedioxy acid The results show that 2- (phosphonomethyl) pentanedioic acid exhibits a high inhibitory activity of NAALADase, with a Kj. of 0.293 Nm. The activity of this compound is more than 1000 times greater than that previously described for NAALADase inhibitors. In comparison, 2- (phosphonomethyl) succinic acid exhibits a much lower inhibitory activity of NAALADase, suggesting that an analogous glutamate bound to phosphonic acid contributes to its inhibitory activity of NAALADase. The results also show that 2- [[(2-carboxyethyl) -hydroxyphosphinyl] methyl] pentanedioic acid, which has an additional carboxylic acid side chain similar to that of the aspartate residue found in NAAG, exhibits a lower inhibitory activity of NAALADase than that of 2- (phosphonomethyl) pentanedioic acid. Protocol for the In Vitro Assay of the Inhibition of NAALADase Activity The amount of [3H] Glu released from [3H] NAAG in Tris-C150 Mm regulator was measured for 15 minutes at 37 ° C using 30-50 μg of protein synaptosomal The substrate and the product were analyzed by liquid anion exchange chromatography. Tests were performed in duplicate so that no more than 20% of the NAAG was digested, representing the linear range of peptidase activity. Quiscualate (100 μM) was included in parallel test tubes to confirm the specificity of the measurements. In Vitro Assay of NAALADase Inhibitors in Ischemia To examine the in vitro effect of NAALADase inhibitors in ischemia, cultures of cortical cells were treated with various compounds of formula I during an ischemic attack (potassium cyanide and 2-deoxyglucose) and for one hour afterwards (for experimental details, see Vornov et al., J. Neurochem, Vol., 65, No. 4, pp. 1681-1691 (1995)). The neuroprotective effect of each tested compound is given below in Table III (a). The neuroprotective effect is expressed as EC50, the concentration that is required to cause a 50% reduction in glutamate toxicity after an ischemic attack.

TABLE III (a) Compound EC? 0 (Nm) 100 The dose response of this effect, as measured by the% toxicity at different concentrations of 2- (phosphonomethyl) pentanedioic acid, is given in the following TABLE III ( b) and presented graphically in Figure I. TABLE III (b) Dosage% Toxicity Control 100.00 + 9.0 (n = 5) 100 Pm 66.57 + 4.38 (n = 5) 1 Nm 42.31 + 9.34 (n = 5) 10 Nm 33.08 + 9.62 (n = 5) 100 Nm 30.23 + 9.43 (n = 5) 1 μM 8.56 + 8.22 (n = 5) The results show that the toxicity decreases when the concentration of 2- (phosphonomethyl) pentanedioic acid increases, suggesting that the inhibitors of NAALADase would be effective in the treatment of ischemia or neuronal damage caused by ischemia. The methods for this test are described in detail later. Specifically, cell cultures were exposed to potassium cyanide and 2-deoxyglucose (2-DG) (10 mm) and analyzed by lactate dehydrogenase (LDH) release. In Vitro Toxicity of NAAG To examine the in vitro toxicity of NAAG, cortical cell cultures were treated with NAAG mixtures (in concentrations ranging from 3 μM to 3 mm) for 20 minutes. The toxicity measurements for each NAAG concentration are given below in TABLE IV and are presented graphically in Figure 2. TABLE IV NAAG dose Toxicity% 3 μM 3.51 (n = 1) 10 μM 4.30 ± 3.12- (n = 3) 30 μM 11.40 ± 6.17 (n = 3) 100 μM 12.66 ± 5.50 (n = 3) 300 μM 13.50 ± 4.0 (n = 3) 1 mm 21.46 + 4.20 (n = 3) 3 mm 45.11 ± 4.96 (n = 3) The results show that the toxicity increases when the concentration of NAAG increases. The toxicity is attributed to the release of glutamate by NAAG when it is cut by NAALADase. In Vitro Assay of NAALADase Inhibitors on NAAG Toxicity To examine the effects of inhibitors of NAALADase on in vitro toxicity of NAAG, cultures of cortical cells were treated with 2- (phosphonomethyl) pentanedioic acid (1 μM) during exposure to NAAG and for an hour later. The toxicity measurement for each NAAG concentration is given below in TABLE V and is presented graphically in Figure 3. TABLE V NAAG dose Toxicity% 3 μM 4.71 (n = 1) 10 μM 3.08 ± 0.81 (n = 3 ) 30 μM 4.81 i 1.13 (n = 3) 100 μM 2.87 ± 0.78 (n = 3) 300 μM 2.09 + 0.48 (n = 3) 1 mm 0.26 ± 1.11 (n = 3) 3 mm 16.83 ± 8.76 (n = 3) ] When comparing the results of FIGURE 2 / TABLE IV, the results of FIGURE 3 / TABLE V show that the toxicity decreases considerably after treatment with the NAALADase inhibitor, suggesting that it would be effective in the treatment of glutamate abnormalities. N Vitro Assay of NAALADase Inhibitors in Ischemia at Different Administration Times To examine the effect of NAALADase inhibitors on ischemic toxicity in vitro at different administration times, cortical cell cultures were treated with 2- (phosphonomethyl) acid. pentane dioxide (i) du during an ischemic attack and for an hour afterwards (exposure and recovery); (ii) for one hour after the ischemic attack (recovery only); and (iii) for one hour beginning 30 minutes after the ischemic attack (delayed 30 minutes). The toxicity measurement for each administration time is provided later in TABLE VI and is presented graphically in FIGURE 4. TABLE VI Time of Administration Relating to Ischemic Attack% Toxicity Control 100.00% EExxppoossiicciiónn yy RReeccuuppeerraacciióónn 2.54% Recovery Only 9.03% Delayed 30 Minutes 31. 9% The results show that significant neuronal protection is achieved when NAALADase inhibitors are administered during the exposure and recovery from an ischemic attack, and even after a delay of 30 minutes after the ischemic attack. Protocol for the In Vitro Toxicity Test a. Cell culture Dissociated cortical cell cultures are prepared using the papain-dissociation method of Heuttner and Baughman (1986) as modified by Murphy and Baraban (1990). See TABLE VII for the Dissociated Cultivation Protocol as used herein. Fetuses of embryonic day 17 of pregnant rats (Harían Sprague Dawley) are removed. The cortex is rapidly dissected in saline solution regulated by Dulbecco's phosphates, released from meninges, and incubated in a papain solution for 15 minutes at 37 ° C. The fabric is then mechanically crushed and pelletized at 500 g (1000-2000 rpm on a Beckman tray). The pellet is resuspended in a DNase solution, crushed with a 10 ml xl5-20 pipette, layered on a "10 x 10" solution containing albumin and trypsin inhibitor (see TABLE VII for an example of a solution of 10 x 10"), turned into pellet, and resuspended in a plate medium containing 10% fetal bovine serum (HyClone A-III-L), 5% heat-inactivated equine serum (HyClone A-3311-L ), and 84% of modified Earle's basal medium (MEM) (Gibco 51200-020) with high glucose (4.5 g / L), and 1 g / L NaHC03. Each 24-well plate is pretreated with poly-D-licina (0.5 ml / 10 μg / ml pszo) for 1 hour and washed with water before striating. The cultures are striated at 2.5 x 106 cells / ml with each well of a 24-well plate receiving 500 μl / well. Alternatively, 35 mm discs may be scored at 2 ml / disc, 6 plate wells at 2 ml / well, or 12 plate wells at 1 ml / well. After striatum, 50% of the medium is changed every 3-4 days with growth serum containing 5% heat inactivated equine serum (HyClone A-3311-L), 95% modified Earle's basal medium (MEM) (Gibco) 51200-020), and that of L-Glutamine l.

(Gibco 25030-081). The experiments are carried out after 21 days in culture. The cultures are maintained in a 5% C02 atmosphere at 37 ° C. These methodologies are further described in detail later in TABLE VII. TABLE VII DISSOCIATED CULTURE PROTOCOL Pattern 10 and 10, 10 ml Pattern of poly-D-Lysine, 5 ml 100 mg BSA (Sigma A-4919); 5 mg of Poly-D-Lysine- 100 mg of 100-150 K Inhibitor (Sigma P-6407); Egg white trypsin 5 ml sterile water (Sigma T-2011); keep frozen 10 ml of dissociated EBSS; sterile filter.

DISSOCIATED CULTURE PROTOCOL Medium Dissociated growth, 500 ml Striae medium. 300 ml 500 ml MEM (Gibco 51200-020) 250 ml of the containing MEM containing glucose and NaHCl3 glucose and sodium bicarbonate (2.25 gm of glucose and 0.5 gm of (2.25 gm of glucose and 0.5 gm NaHC03) 25 ml heat-inactivated NaHC03 in 500 ml Gibco Equine Serum (HyClone A-3311-L); MEM 51200-020); 5 ml L-Glutamine (200 Mm, standard 30 ml Fetal Bovine Serum 10 ° x, Gibco, 25030-081); filter (HyClone A- l l l l-L). sterile 15 ml inactivated by heat. Horse serum (HyClone A-3311-L); 3 ml L-Glutamine (200 Mm, standard lOOx, Gibco, 25030-081); (Gibco 15140-015); DISSOCIATED CULTIVATION PROTOCOL For papain dissociation: For DNase treatment: 4 mg Cysteine (C 8277); DNase. 5 ml 25 ml of dissociated EBSS; 4.5 ml. EBSS dissociated; 250 μl Papain pattern 500 μl of pattern "10 and 10"; (orthington LS003126); 50 μl DNase standard place in water bath at "10 and 10" 5 ml 37 ° C until clear. 4.5 ml of EBSS; 500 μl of pattern "10 and 10" II. CULTIVATION PLATE COATING Use poly-d-lysine standard at a dilution to cover 24 wells (0.5 ml / well) or 1:10 dilution to cover 35 mm glass coverslips (1.0 ml / well) - objects, leave until the end of the dissection.

DISSOCIATED CULTIVATION PROTOCOL III. STRAIGHT FABRIC Use pregnant rats would Sprague-Dawley ordered to reach E-17. Decapitate, spray abdomen with 70% EtOH.

Remove uterus through a midline incision and place in sterile DPBS. Remove the brains from the embryos by leaving them in DPBS. Brain Removal: Penetrate the skull and skin with fine forceps in lambda. Push to open the posterior fossa.

Then move in forceps to separate the sagittal suture. The brain can be removed by digging from the olfactory bulbs below the brain. Move 1 < DS brains to DPBS. Fresh, subsequently, dissect from the cortex.

DISSOCIATED CULTIVATION PROTOCOL IV. DISSOCIATION D? PAPAINA Transfer the cortices equally to two 15 ml tubes containing sterile papain solution, maintained at 37 ° C • Triturate xl with a sterile 10 ml pipette. Incubate only for 15 minutes at 37 ° C. It was rotated at 500 G for 5 minutes (1000-2000 RPM on a 1-cup Beckman bucket). V. TREATMENT D? DNase Remove excess and any DNA gel layer from the cell pellet (or lift and remove the pellet with the pipette). Move the pellet of cells to the DNA solution asa.

Grind with 10 ml pipette, xl5-20. Place the cell suspension on the "10 and 10" solution by pipetting it against the side of the tubes. Turn again at 500 G for 15 minutes (the cells will rotate inside the "10 and 10" layer) • Wash the sides of the tubes with half-flutes without disturbing the pellet. Pipette the washing medium and repeat the washing DISSOCIATED CULTIVATION PROTOCOL SAW . PLATE Add approximately 4.5 ml of stria medium to each pellet for 5 ml volume. Resuspend with 10 ml pipetting Gather cells in a single tube. Quickly add 10 μl of the suspended cells to a hemocytometer so that they do not settle. Count the cells by large square, corresponding to 10 million cells / ml. Place the resuspended cells inside a larger container so that they are 2.5 million cells / ml. Grind until homogeneous. Finish covering the plates: Aspirating or emptying licina; Wash xl with sterile water and empty Ag irrigate half stria, with cells, to the plates as mm dishes 2 ml / dish; 6 well pond 2 ml / well; 12 well blade 1 ml / well; 24 well paddle 500 μl / well.

DISSOCIATED CULTIVATION PROTOCOL VII. FOOD Crops are usually done on Thursdays. Start feeding twice a week; Beginning the following Monday, feeds on Monday and Friday - Remove 50% of the volume and replace with fresh growth medium. b. Ischemic attack using potassium cyanide and 2-deoxyglucose - The experiment is carried out twenty-one to twenty-four days after the striation of initial cortical cells. The cultures are washed three times in HEPES regulated with saline solution that does not contain phosphate. The cultures are then exposed to potassium cyanide (KCN) (5 mm) and 2-deoxyglucose (2-DG) (10 mm) for 20 minutes at 37 ° C. These concentrations previously showed to induce maximum toxicity (Vornov et al., J. Neurochem, Vol. 65, No. 4, pp. 1681-1691 (1995)). At the end of 24 hours, the cultures were analyzed by release of the enzyme cytosolic lactate dehydrogenase (LDH), a standard measure of cell lysis. LDH measurements are made according to the method of Koh and Choi, J., Neuroscience Methods (1987). c. Neurotoxicity Induced by NAAG The cultures are evaluated microscopically and those with uniform neuronal densities are used in the neurotoxicity assays of NAAG mixtures. At the time of the experiment, the cultures are washed once in regulated saline-HEPES (HBSS, 143.4 mM NaCl, 5 mM HEPES, 5.4 mM KCl, 1.2 mM MgSO4, 1.2 mM NaH2P04, 0. 0 mM CaCl2 , 10 mM D-glucose) (Vornov et al., 1995) and then exposed to various concentrations of NAAG for 20 minutes at 37 ° C. NAAG concentrations range from 3 μM to 3 mm, and include 3 μM, 10 μM, 30 μM, 100 μM, 300 μM, 1 mm, and 3 mm. At the end of the exposure, the cells are washed once with HEPES regulated saline and then replaced with serum-free Earle's medium modified. The cultures are then returned to the CO incubator? for 24 hour recovery. d. Lactate Dehydrogenase Assay The release of the enzyme cytosolic lactate dehydrogenase (LDH), a standard measure of cell lysis, is used to quantify the damage (Koh and Choi, 1987). Measurements of LDH activity are normalized to control the variability between culture preparations (Koh and Choi, 1987). Each independent experiment contains a control condition in which no inhibitors are added.

NAALADase; A small amount of LDH activity is found in these controls. This control measure is subtracted from each experimental point. These values are normalized within each experiment as a percentage of the damage caused by NAAG / ischemia. Only the main effects of NAALADase inhibitors are considered; Interactions between dose and condition are not examined statistically. A measure of the potency of each tested compound is made by measuring the percentage of LDH release within the growth medium after exposure to NAAG / ischemia in addition to the NAALADase inhibitor or NAAG / ischemia in addition to saline (control). Since high concentrations of glutamate can be toxic to cells under certain circumstances, the measurement of glutamate toxicity is observed using LDH as a standard measurement technique. In Vivo Assay of NAALADase Inhibitors in Cortical Damage after MCAO in SHRSP rats To examine the effect of NAALADase inhibitors on cortical damage in vi, that they have had occlusion of the middle cerebral artery (MCAO) and that they have been treated subsequently with (i) saline; (ii) 10 mg / kg of 2- (phosphonomethyl) pentanedioic acid followed by 2 mg / kg / hr of 2- (phosphonomethyl) pentanedioic acid for 1 hour; s (iii) 100 mg / kg of 2- (phosphonomethyl) pentanedioic acid followed by 20 mg / kg / hr of 2- (phosphonomethyl) pentanedioic acid for one hour. The volume of cortical damage for each rat group is given later in TABLE VIII and is presented graphically in Figure 5. TABLE VIII The results show that the volume of cortical damage decreased and cortical protection increased when the amount of NAALADase inhibitor increased, further supporting the neuroprotective effect of the NAALADase inhibitor. Protocol for the Live Test of NAALADase Inhibitors in Cortical Damage A SHRSP rat colony is reproduced at the Johns Hopkins School of Medicine from three pairs of male and female rats obtained from the National Institutes of Health (Laboratory, Section of Science, Veterinary Resources Program, National Center for Research Resources, Bethesda, MD). All rats are kept in a virus-free environment and maintained on a 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 (MCA) is induced by advancing a 4-0 surgical nylon suture within the internal carotid artery (ICA) to block the origin of the MCA (Koizumi, 1986, Longa, 1989, Chen, 1992). ). The rats were anesthetized with 4% halothane, and maintained with 1.0% up to 1.5%. of halothane in air enriched with oxygen using a mask. The rectal temperature is maintained at 37.0 ± 0.5 ° C through the surgical procedure using a heating lamp. The right femoral artery is voided for the measurement of blood gases (Ph, oxygen tension [P02], carbon dioxide tension [PC02]) before and during ischemia, to monitor blood pressure during surgery. The right common carotid artery (ACC) is exposed through a midline incision; A retractor retractor is placed between the digastric and mastoid muscles, and the muscle or ohioid is divided. The right external carotid artery (RCT) is dissected and ligated. The branch of the occipital artery of the ECA is then isolated and coagulated. Then, the right internal carotid artery (ICA) is isolated until the pterygopalatine artery is exposed, and it is carefully separated from the adjacent vagus nerve. The pterygopalatine artery is ligated with 4 0 silk suture near its origin. After the ACC is ligated with 4-0 silk suture, a 4-0 silk suture to prevent puncture site bleeding, through a 4-0 monofilament nylon suture 2.5 cm in length (Ethilon) , its tip rounded by heating near an electric cauterizer, is introduced into the ICA lumen. A 6-0 silk suture was wrapped around the intraluminal nylon suture at the bifurcation to prevent bleeding, and narrowed sutures were released in the ACC and ICA. The nylon suture is then gently advanced as much as 20 mm. Anesthesia was terminated after 10 minutes of MCA occlusion in both groups, and the rats were awake 5 minutes later. After 2 hours of ischemia, anesthesia is re-anesthetized, and reperfusion is performed by removing the intraluminal nylon suture until the distal tip becomes visible at the origin of the AHF. The arterial Ph and PaCO, and the partial pressure of oxygen (Pa02) were measured with a self-calibrating radiometer electrode system (ABL 3, Copenhagen, Denmark). The hemoglobin and arterial oxygen content was measured with a hemoximeter (Radiometer, Model OSM3, 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 except the rectal temperature were measured at the baseline at 15 minutes and 45 minutes from the right MCA occlusion. The rectal temperature was measured in the baseline at 0 and 15 minutes of occlusion of MCA, and at 0 and 22 hours of reperfusion. In Vivo Assay of NAALADase Inhibitors on Brain Damage after MCAO in Sprague-Dawley Rats To examine the neuroprotective effect of NAALADase inhibitors on brain damage in vivo, Sprague-Dawley rats were treated with a vehicle or 2- (phosphonomethyl) acid. ) pentanedioic before and after sustaining a transient 2-hour medial cerebral artery occlusion (MCAO). In the control group (n = 8), the rats received an IP injection of saline 30 minutes post-occlusion followed by IV saline infusion at a rate of 0.5 ml / hr.

In the drug-treated groups, the rats received an IP injection of 2- (phosphonomethyl) pentanedioic acid at a dose of 100 mg / kg at 20 minutes pre-occlusion (n = 5), 30 minutes post-occlusion (n = 9), 60 minutes post-occlusion (n = 7), or 120 minutes post-occlusion (n = 4), followed by an IV infusion of 20 mg / kg / hr for 4 hours (infusion rate = 0.5 ml / hr). There was a 15 minute delay between IP and IV treatments for each rat. Twenty-two hours after reperfusion, the rats were euthanized and their brains were removed. Seven coronal sections (2 mm thick) were taken and stained with 1% solution of 2, 3, 5-triphenyltetrasoleo chloride (TTC) for 20 minutes and then in 10% formalin. The anterior and posterior duferficie of the most rostrated brain section and the posterior surface of each of the other 6 sections were represented by an image. The quantification of the infarct size of each brain was obtained using a computer-assisted digital image analysis system (LOATS). Brain regions completely devoid of TTC-staining were characterized as representative of infarcted tissue. The total infarct volume for each rat was calculated by the numerical integration of the respective sequential areas of the brain. The total infarct volume for each group of rats is plotted in FIGURE 6. The vehicle-treated rats exhibited mean total brain infarct volume of 293 ± 26 mm3. Rats treated with 2- (phosphonomethyl) pentanedioic acid before or after the ischemic attack had mean total brain infarct volumes significantly lower than 122 ± 26 mm3 (p = 0.003 vs. vehicle) for the pre-treatment of 20 minutes, 208 ± 40 mm3 (p = 0.2 vs. vehicle) for the post-treatment of 30 minutes, 125 ± 57 mm3 (p = 0.015 vs. vehicle) for the post-treatment of 60 minutes, and 133 ± 35 mm3 (p = 0.005 vs. vehicle) for the 120-minute post-treatment. These results indicate that 2- (phosphonomethyl) pentanedioic acid is neuroprotective in the rat MCAO apoplectic model when administered two hours after occlusion. Protocol for a live Jn assay of NAALADase inhibitors in Brain Injury Male Sprague-Dawley rats (260-320 g) were used. Before the experiment, the rats were housed individually and allowed free access to food and water. Each rat received two surgeries: cannulation of the jugular vein for IV infusion and MCAO. During surgeries, the rat was anesthetized with 2% halothane supplied in oxygen through an inhalation mask. Body temperature was monitored and regulated at normal temperature using a homeothermic heating system. First, a polyethylene catheter was inserted into PE-50 into the right jugular vein. One hour later the rat was reanestiated for surgeries in MCAO mixtures. The MCAO was achieved using an endovascular suture method described by Long et al., Stroke, Vol. 20, pp. 84-91 (1989) '. Specifically, the coagulated and transected right external carotid artery (RCT) was exposed. A 3-0 monofilament of nylon suture with a blunt tip was inserted into the proximal ACE stump by an arteriotomy and advanced 20 mm from the bifurcation of the carotid until it lodged in the proximal region of the cerebral artery. previous, which occluded the origin of the MCA. The rats were allowed to wake up; 2 hours later, the rats were re-anesthetized for reperfusion, during which the nylon suture was retracted from the ACE stump allowing recirculation of the blood to the MCA.

Jn Live Trial of NAALADase Inhibitors in Stroke Induced by Elevation of Glutamate Levels in the Brain. To examine the effect of NAALADase inhibitors in hyperglutamatergic disorders in vivo, rats were treated with apoplexy induced by elevation in brain glutamate levels with a vehicle or 2- (phosphonomethyl) pentanedioic acid. The results are presented graphically in Figures 7, 8 and 9. The results show that the treatment with 2- (phosphonomethyl) pentanedioic acid (100 mg / kg IP followed by 20 mg / kg / hr IV) significantly attenuates the apoplexy induced by increases in extracellular glutamate in the striatum (FIGURE 7) when compared to the vehicle-treated rats (p <0.05), and completely prevent changes in concurrent glutamate in the parietal cortex (p <0.01; FIGURE 8). In contrast, there was no significant effect on stroke itself on glutamate in the frontal cortex and no subsequent difference between the groups treated with 2- (phosphonomethyl) pentanedioic acid and the vehicle (FIGURE 9). The values are expressed as% of baseline where the baseline constitutes the average of three consecutive samples of 20 minutes before the stroke. The absolute basal values (pretreatment) for glutamate (mean ± SEM) in caudate, parietal and frontal cortices were 0.25 + 0.1, 1.1 + 0.3 and 0.6 + 0.1 μM, respectively, in rats treated with vehicle, and 0.46 + 0.1 , 2.0 + 0.7 and 0.9 + 0.3 μM, respectively, in the rats treated with 2- (phosphonomethyl) pentanedioic acid. Protocol for the Live Jn Assay of NAALADase Inhibitors on Elevation-Induced Shock in the Glutamate Levels in the Brain. Male Sprague Dawley rats (270-330 g, n = 5-6 per group) were implanted with concentric microdialysis probes similar to the procedures previously described (Britton et al., J. Neurochem., Vol. 67, pp. 324 -329 (1396)). In short, under halothane anesthesia, probes were implanted (constructed at home using Caprophane capillary membrane, cut 10K mw, 2 mm dialyzing length) inside the frontal cortex (AP = + 3.5, ML = 3, DV = 3), nucleus caudate (AP = 0, ML = 3, DV = 6.6), and parietal cut (AP = -2, ML = 5, DV = 3) (coordinates in mm relative to the vertex and dura, respectively), regions that are believed they represent the areas of the nucleus and penumbra of the damage induced by ischemia. The glutamate levels in the dialysate were determined using precolumn o-Ptaldialdehyde derivation, followed by HPLC with fluorometric detection. Approximately 20 hours after the implantation of the probe, the rats were dialyzed with perfusion fluid (125 Mm NaCl, 2.5 Mm KCl, 1.18 Mm MgCl 2 and 1.26 Mm CaCl 2) at a rate of 2.5 μl / min. After a stabilization period of 60 minutes, the dialysis samples were collected every 20 minutes. After collecting 3 baseline samples, the rats were anesthetized with halothane and subjected to temporal ischemia using the MCAO filament method (Britton et al., Life Sciences, Vol. 60, No. 20, pp. 1729-1740 (1997)). In short, the right external carotid artery (RCT) was exposed and its branches coagulated. A 3-0 monofilament of nylon suture was introduced into the internal carotid artery by means of an arteriotomy in the ACE and advanced until it lodged in the proximal region of the anterior cerebral artery, thus occluding the origin of the ACM. The endovascular suture was retracted to allow reperfusion 2 hours after occlusion. Body temperature was maintained at normal temperature through stroke surgery and reperfusion procedures. The rats were dosed IP with 100 mg / kg of 2- (phosphonomethyl) pentanedioic acid at -20 minutes of preocclusion and IV at 20 mg / kg / hr for 4 hours at the time of occlusion. The dialysis samples were collected every 20 minutes from the non-anesthetized rats. After 24 hours of repurfusion, 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 cortical junction. -cerebeling The analysis of the cerebral brain damage was achieved using TTC staining and computer-assisted imaging analysis as described by Britton et al. (1997), supra. Living Jn Assay of NAALADase Inhibitors on M Formation, Ielin After Sciatic Nerve Cryoliation It was recently shown that NAALADase is down-regulated in glial cells when they begin to form myelin and is absent in Schuann myelination cells. Based on these data, the inventors hypothesized that the inhibition that NAALADase can affect the signal mechanism between axons and Schuann cells and results in increased myelination. To test this hypothesis, the inventors examined the effect of 2- (phosphonomethyl) pentanedioic acid on nerve regeneration and myelination after cryosurgery of the sciatic nerve in male mice. The results are given later in TABLE IX and are presented graphically in FIGURE 10 (a) and FIGURE 10 (b). TABLE IX JN LIVE EFFECT OF NAALADASA INHIBITORS ON TRAINING MYELIN AFTER CRIOLESION OF THE STIC NERVE Acid 2- (phosphonomethyl) Vehicle Pentanodium Ratio of # of axons 1.5 Wedge (drug / vehicle) # of thin layer honeydew 16.53 + 0.65 13.77 + 0.09 (average + SEM)% increase in thin layer 20 % myelinated on the vehicle Significance by the p < 0.005 test t. As detailed in FIGURE 10 (a) and FIGURE (b), examination by electron microscopy and electron transmission (TEM) of the 3 mm distal nerve at the site of cryolysis showed a significant increase in the number of myelinated axons (1.5 fold increase) and thickness of myelin (20 % increase, p <0.005), compared to the nerves of the mice treated with vehicle. FIGURE 10 (a) and FIGURE 10 (b) show a photomicrograph of this effect. Sections were stained with tolidine blue which stains the myelin. The sciatic nerves treated with 2- (phosphonomethyl) -pentanedioic acid contain implants, compared to the sciatic nerves treated with implant containing vehicles, showed an increase in the number of myelinated axons as well as an increase in the thickness of the myelin.

Protocol for the In Vivo Assay of NAALADase Inhibitors on the Myelin Formation After Cryolesion of the Sciatic Nerve. The cryosurgery of the sciatic nerve of the mouse is performed according to Koenig et al., Science, Vol. 268, p. 1500-1503 (June 1995). In brief, each mouse was anesthetized and its sciatic nerve was exposed in the upper thigh and was cryolized using copper cryode (diameter = 0.5 mm) which was soaked in liquid nitrogen and applied repeatedly to the upper part of the nerve. The extent of the lesion was approximately 1 mm. 2- (Phosphonomethyl) pentanedioic acid was incorporated into silicone strips according to the method of Connold et al., Devel opmental Bra in Res., Vol. 28, pp. 99-104 (1986), and was implanted at the site of cryolysis on day 0 and renewed on days 3, 6, 9 and 12. Approximately 2.5 μg / day of 2- (phosphonomethyl) -pentanedioic acid was released from the silicone implants every day. The right and left sciatic nerves of each mouse were injured; the right side nerves were treated with silicone implant strips containing vehicle alone while the nerves on the left side were treated with silicone implants containing 2- (phosphonomethyl) pentanedioic acid. Fifteen days after the surgery, the mice were sacrificed and their sciatic nerve segments were collected and processed for optical microcosm analysis and TEM analysis. Randomly chosen fields of 2-3 mm distal to the lesion were qualitatively analyzed by optical microcosm using cross sections of a micrometer thick stained with tolidine blue and photographic images were captured. Living Jn Assay of NAALADase Inhibitors in Parkinson's Disease To examine the effect of NAALADase inhibitors on Parkinson's Disease in vivo, MPTP-injured mice were treated with 2- (phosphonomethyl) pentanedioic acid or a vehicle. The percentage of dopaminergic neurons for each group of mice is given later in TABLE X and is presented graphically in FIGURE 11. TABLE X JN LIVE EFFECT OF NAALADASA INHIBITORS ON PARKINSON'S DISEASE Percent of Innervation Density TH Strial. (mean ± SEM) Vehicle / Vehicle 2 .74 ± 1.03 MPTP / Vehicle 7.82 ± 0.68 MPTP / Acid 2- (phosphonomethyl) - 16.28 + 0.98 Pentanodioic.

Mice treated with MPTP and vehicle showed a substantial loss of dopaminergic functional terminals compared with non-injured mice (approximately 69% loss). The injured mice received 2- (phosphonomethyl) pentanedioic acid (10 mg / kg) showed a significant recovery of dopaminergic neurons stained -TH (p < 0.001). These results indicate that 2- (phosphonomethyl) pentanedioic acid protects against MPTP toxicity in mice. Protocol for the In Vivo Assay of NAALADase Inhibitors in Parkinson's Disease The MPTP injury of dopaminergic neurons in mice was used as an animal model of Parkinson's Disease, as described by Steiner, Proc. Na ti. Acad. Sci. , Vol. 94, pp. 2019-2024 (March 1997). In short, four-week-old male CDI white mice were dosed IP with 30 mg / kg MPTP for 5 days. SC 2- (phosphonomethyl) pentanedioic acid (10 mg / kg) or a vehicle was administered along with the MPTP for 5 days, as well as for an additional 5 days after cessation of MPTP treatment. At 18 days after the MPTP treatment, the mice were sacrificed and their brains were removed and sectioned. Immunostaining was performed on the sagittal and coronal sections of the brain using anti-tyrosine hydroxylase (TH) antibodies to quantify the survival and recovery of dopaminergic neurons. In Vivo Assay of NAALADase Inhibitors in Dynorphin Induced Damage in the Spinal Cord To examine the neuroprotective effect of NAALADase inhibitors on excitotoxic damage in spinal cord In vi vo, rats that have had spinal cord damage induced by dynorphin are treated with a vehicle or 2- (phosphonomethyl) pentanedioic acid. The results are presented graphically in the FIGURE 12. When co-administered with dynorphin A, 2- (phosphonomethyl) pentanedioic acid (4 μmol) caused significant improvement in motor results during 24 hours post-injection, compared to the vehicle-treated rats (p <0.05, Kruskal-allis comparison). The rats were characterized as ambulatory or not based on their assigned neurological results (0 to 4). At 24 hours post-injection, 73% of the 15 rats co-treated with 2- (phosphonomethyl) pentanedioic acid were ambulatory, in contrast to 14% of the 14 rats co-treated with vehicle (p <0.05). These results indicate that 2- (phosphonomethyl) pentanedioic acid provides effective protection against dynorphin induced damage in the spinal cord.

Protocol for the In Vivo Assay of NAALADase Inhibitors on Dynorphin Induced Damage in Spinal Cord Spinal Subarachnoid Injections The dynorphin-induced damage of the spinal cord was performed according to Long et al., JPET, Vol. 269, No. 1 , pp. 358-366 (1993). In brief, spinal subarachnoid injections were delivered using measurement needles 30 inserted between the L4-L5 vertebrae of male Sprague-Dawley rats (300-350 g). The rats were anesthetized with halothane and incisions were made from the dorsal midline and immediately rostral to the pelvic girdle. Using the vertebral processes as a guide, the needle was advanced to pass within the arachnoid space surrounding the cauda equina. The correct placement of the needle was verified by the CSF flow of the needle after its insertion. The injections were delivered using a Hamilton microsyringe in a total volume of 20 μl which contained dynorphin (20 nmol), the cannula was flooded and 2- (phosphonomethyl) pentanedioic acid or vehicle. After the injections, the incisions were treated with the local antibacterial furazolidone and fastened with wound clips. Rapid recovery from halothane anesthesia allowed neurological evaluations to be made at 5 minutes after injections.

Neurological evaluations. The neurological function was evaluated using an ordinal scale of 5 points, with the results being assigned as follows: 4 = normal motor function; 3 = average paraparesis, with the ability to support weight and walk with deterioration; 2 = paraparesis, with the ability to make movements to walk without fully supporting the weight; 1 = severe paraparesis, in which rats can do limited movement of the hind limb, but no movement of gait; and 0 = flaccid paralysis, with complete absence of any movement of the hind limb. Neurological evaluations were made 24 hours after the injection of dynorphin A. Statistics The differences in neurological outcomes between the treatment groups were determined by means of the U Mann test of hitney or the Kruskal-allis test. In Vitro Assay of NAALADase Inhibitors on Amyotrophic Lateral Sclerosis (ALS) To examine the neuroprotective effect of NAALADase inhibitors on. Amyotrophic Lateral Sclerosis (ALS), organotypic spinal cord cultures were treated with treohydroxyapartate (THA), 2- (phosphonomethyl) pentanedioic acid, or THA combined with 2- (phosphonomethyl) pentanedioic acid, and assay by activity of colin acetyltransferase (ChAT) ).

The ChAT activity for each treatment of the organotypic cultures of the spinal cord is given below in TABLE XI and is presented graphically in Figure 13. TABLE XI NEUROPROTECTOR EFFECT OF INHIBITORS OF NAADASE IN THE MODEL OF CULTURE D? MEDULA? SPINAL D? ALS Treatment Activity ChAT (% control) control 100 ± 22.1 2- (phosphonomethyl) -pentanedioic acid only 108 ± 18.4 THA only 36 ± 12.1 2- (Phosphonomethyl) -pentanedioic acid and THA 121 ± 18.8 As shown in FIGURE 13, treatment of organotypic cultures of the spinal cord with 100 μM THA resulted in a reduction in ChAT activity in approximately 36% of the control cultures. Incubation of the cultures with THA and 2- (phosphonomethyl) pentanedioic acid (100 Nm 10 μM) significantly protecting the cultures from THA toxicity. The response to the dose of this effect is given later in TABLE XII and is presented graphically in FIGURE 14.

TABLE XII NEUROPROTECTOR EFFECT D? THE INHIBITORS OF NAALADASADA IN? L MOD? LO D? CULTURE D? MEDULA? SPINAL D? ALS ChAT activity (% control) CONTROL 100.0 THA 0 THA and INm 2- (phosphonomethyl) pentanedioic acid - -23.9 ± 18.6 THA and lONm 2- (phosphonomethyl) pentanedioic acid 23.1 ± 12.5 THA and lOONm 2- (phosphonomethyl) pentanedioic acid 87.5 ± 21.7 THA and IμM 2- (phosphonomethyl) pentanedioic acid 187.7 ± 32.8 THA and lOμM 2- (phosphonomethyl) pentanedioic acid 128.7 ± 17.2 The spinal cord cultures were incubated with various doses of 2- (phosphonomethyl) pentanedioic acid (1 Nm to 10 μM) in the presence of THA (100 μM) for 14 days. As shown in FIGURE 14, 2- (phosphonomethyl) pentanedioic acid exhibited dose-dependent protection against THA-induced toxicity with maximum effects at 1 μM. Protocol for In Vivo Assay of NAALADase Inhibitors on Amyotrophic Lateral Sclerosis (ALS) Organotypic Spinal Cord Crops Organotypic cultures of lumbar spinal cord of 8-day-old rats were prepared as described by Rothstein et al., J. Neurochem. , Vol. 65, No. 2 (1995), and "V Rothstein et al., Proc. Na ti. Acad. Sci. USA, Vol. 90, pp. 6591-6595 (July 1993). they removed lumbar spinal cords and were sliced in ventral-dorsal sections of 300 μM thickness, and 5 slices were placed on CM semipermeable diameter 30 mm membrane inserts.The inserts were placed on 1 ml of culture medium in wells of culture The culture medium consisted of 50% minimal essential medium and phosphate-free HEPES (25 mm), 25% heat-inactivated horse serum, and 25% Hank's balanced salt solution (GIBCO). supplemented with D-glucose (25.6 mg / ml) and glutamine (2 mm), for a final Ph of 7.2. No agents, fungi and antibiotics were used. The cultures were incubated at 37 ° C in a humidified environment containing 5% CO? (Scientific Form). The culture medium, together with any added pharmacological agents, was changed twice a week. Chronic Toxicity Model with THA For all experiments, the cultures were used 8 days after the preparation, at which time treohydroxiaspartate (THA) was added to the culture medium.; 100 μM), 2- (phosphonomethyl) pentanedioic acid (100 Pm 10 μM), or THA (100 μM) + 2- (phosphonomethyl) pentahodioic acid (100 Pm-10 μM). The drugs were incubated for an additional 13 to 20 days with 100 μM THA. At the end of this period, the cultures were harvested and tested by ChAT activity as described below. ChAT Assays To determine the activity of colin acetyltransferase (ChAT), the spinal cord tissues in each dish (5 slices) were collected and frozen (75 ° C) until assay. The ChAT activity was measured radiometrically by the methods described using [3H] acetyl-CoA (Amersham; Fonnum, 1975). The protein content of the tissue homogenate was determined by a Coomassi team "Protein Assay (Pierce, Rockford, IL) In Vivo Assay of NAALADase Inhibitors on Ethanol Consumption in Alcohol Preferred Rats To test the effect of the inhibitors of NAALADase on ethanol consumption, rats that prefer alcohol with saline or a dose of 50, 100 or 200 mg / kg of 2- (phosphonomethyl) pentanedioic acid before ethanol access were treated. of the treatment was presented graphically in FIGURE 15. As shown in FIGURE 15, the dose of 200 mg / kg of 2- (phosphonomethyl) pentanedioic acid showed no effect, while doses of 50 and 100 mg / kg significantly reduced ethanol consumption by approximately 25% (p <0.05) during the access period of 1 hour. The body weights, the water consumption of 24 hours were not altered in any of the three doses. If 2- (phosphonomethyl) pentanedioic acid is acting centrally, these data suggest that NAALADase may be involved in neuronal systems that regulate the behavior of alcohol intake Baseline Saline: 8.9 ± 0.7 200 mg / kg 2- (phosphonomethyl) acid ) pentanedioic: 8 ± 0.5 Saline base line: 7.8 ± 0.8 ^ 100 mg / kg 2- (phosphonomethyl) pentanedioic acid: 5.8 ± 0.7 Saline base line: 8.1 ± 0.6 50 mg / kg 2- (phosphonomethyl) pentanedioic acid: 6.2 ± 0.9 EXAMPLES The following examples are illustrative of the present invention and are not intended to be limitations thereof. Unless stated otherwise, all percentages are based on 100% by weight of the final composition. EXAMPLE 1 Preparation of 2- [(methylhydroxyphosphinyl) methylpentanedioic acid. Scheme IV: R = CH3, R? = CH2Ph Methyl-O-benzylphosphinic acid Dichloromethylphosphite (10.0 g, 77 mmol) was cooled in 80 Ml of dry diethyl ether at -20 ° C under a nitrogen atmosphere. A solution of benzyl alcohol (23 g, 213 mmol) and triethylamine (10.2 g, 100 mmol) in 40 Ml of diethyl ether was added dropwise over 1 hour while maintaining an internal temperature range of 0 ° C to 10 ° C. Once the addition was complete, the mixture was warmed to room temperature and stirred overnight. The mixture was filtered and the solid cake was washed with 200 Ml of diethyl ether. The organics were combined and evaporated under reduced pressure to give 25 g of a clear and colorless liquid. The liquid was purified by flash chromatography and eluted with 1: 1 hexane / ethyl acetate to ethyl acetate gradient. The desired fragments were collected and evaporated to give the methyl-O-becifosphinic acid (1, R = CH3, R? = CH2Ph, 6.5 g, 50%) as a clear and colorless oil. Rf 0.1 (1: 1, Hexane / EtOAc). X H NMR (d 6 DMSO): 7.4 ppm (m, 5 H), 7.1 ppm (d, 1 H), 5.0 ppm (dd, 2 H), 1.5 ppm (d, 3 H) 2,4,4-di (benzyloxycarbonyl) butyl (methyl) acid ) -O-benzylphosphinic Methyl-O-benzylphosphinic acid (3.53 g, 20.7 mmol) in 200 mL of dichloromethane was cooled to -5 ° C under a nitrogen atmosphere. Triethylamine (3.2 g, 32 mmol) was added by injection followed by trimethylsilyl chloride (2.9 g, 27 mmol). The reaction mixture was stirred and heated at room temperature for 1 hour. Dibenzyl 2-methylenepentanedioate (2.06 g, 18.5 mmol) in 10 Ml of dichloromethane was added. The mixture was then stirred overnight at room temperature. The reaction mixture was cooled to 0 ° C and trimethylaluminum (9 Ml, 18 mmol, 2.0 M in dichloromethane) was added. The flask was heated and stirred for 72 hours. The bright light yellow solution was cooled to 5 ° C and quenched by the slow addition of 5% hydrochloric acid. The quenched reaction mixture was heated to room temperature and the organic layer was removed. The organic layer was washed with 5% hydrochloric acid and water. The organics were dried (MgSO 4) and evaporated under reduced pressure to give 8 g of bright light yellow oil. The oil was purified on silica gel and eluted with a gradient of 1: 1 hexanes / ethyl acetate to 100% ethyl acetate. The desired fragments were collected and evaporated to give the 2,4-di (benzyloxycarbonyl) butyl (methyl) -O-benzylphosphinic acid (3, R = CH3, R! = CH2Ph, 0.8 g, 8%) as a clear oil. colorless. Rf 0.5 (ethyl acetate). XH NMR (CDC13): 7.4 ppm (m, 15H), 5.1ppm (m, 6H), 3.0ppm (m, 1H), 2.4ppm (m, 3H), 2.1ppm (m, 3H), 1.5ppm (dd) , 3H). Elemental Analysis Calculated C28H3106P, 0. 5 H20: C, 68. 01; H, 6 3 Found: C, 66.85; H, 6.35. 2- [(Methylhydroxyphosphonyl) methyl] pentanedioic Acid 2 acid, 4-di (benzyloxycarbonyl) butyl (methyl) -O-benzylphosphinic (0.8 g, 1.6 mmol) in 20 Ml of water containing 100 mg of 10% Pd / C was hydrogenated at 40 psi for 4 hours. The mixture was filtered on a pad of Celite and evaporated under high vacuum to give 2- [(methylhydroxyphosphinyl) methyl] pentanedioic acid (4, R = CH 3, 0.28 g), 78% as a clear and colorless viscous oil. 1 H NMR (D 20): 2.5 ppm (m, 1 H), 2.2 ppm (t, 2 H), 2.0 ppm (m, 1 H), 1.7 ppm (m, 3 H), 1.3 ppm (d, 3 H). Elemental Analysis Calculated C7H? A06P, 0.2 H20: C, 36.92; H, 5.93. Found: C, 37.06; H, 6.31. EXAMPLE 2 Preparation of 2- [(butylhydroxyphosphinyl) methyl] pentanedioic acid Scheme IV: R = n-butyl, R? = H Butylphosphinic acid Diethyl chlorophosphite (25 g, 0.16 moles) was cooled in 60 Ml of dry ether at 0 ° C. C under a nitrogen atmosphere. Butyl magnesium chloride was added dropwise (80 Ml, 0.16 moles, 2.0 M solution in ether) over a period of 2 hours while maintaining the internal temperature at 0 ° C. Once the addition was complete the thick white suspension was heated at 30 ° C for 1 hour. The suspension was filtered under a nitrogen atmosphere and the filtrate was evaporated under reduced pressure. The bright light yellow liquid was then treated in 15 Ml of water and stirred at room temperature. Concentrated hydrochloric acid (0.5 Ml) was then added and an exothermic reaction was observed. The mixture was stirred an additional 15 minutes and extracted with two 75 Ml portions of ethyl acetate. The organics were combined, dried (MgSO4) and evaporated to give a clear and colorless liquid. The liquid was treated with NaOH (40 Ml, 2.0 M) and stirred for 1 hour. The mixture was then washed with diethyl ether and acidified to pH 1.0. The desired material was extracted from the acidified extract with two 100 Ml portions of ethyl acetate. The organics were combined, dried (MgSO) and evaporated under reduced pressure to give butylphosphinic acid (1, R = n-butyl, R? = H, 10 g, 51%) as a clear and colorless liquid. 1 R NMR (d 6 DMSO): 6.9 ppm (d, 1 H), 1.6 ppm (m, 2 H), 1.4 ppm (m, 4 H), 0.9 ppm (t, 3 H). Butyl [2,4-di (bensyloxycarbonyl) butyl] phosphinic acid The butylphosphinic acid (2.0 g, 16 mmol) was cooled in 80 ml of dry dichloromethane at 0 ° C under a nitrogen atmosphere. Triethylamine (6.7 g, 66 mmol) was added followed by trimethylsilyl 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) in 20 Ml dichloromethane was added. The cold bath was removed and the reaction was 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 (MgSO4) and evaporated to give a bright golden light liquid. The liquid was purified by flash chromatography and eluted with 3: 1 hexane / ethyl acetate containing 5% acetic acid. The desired fragments were combined and evaporated to give butyl [2,4-di (benzyloxycarbonyl) butyl] phosphinic acid (3, R = n-butyl, R? = H) (2.9 g, 40%) as a clear and colorless oil. Rf 0.12 (3: 1 Hexane / EtOAc, 5% AcOH). X H NMR (d 6 DMSO): 7.3 ppm (m, 10 H), 5.0 ppm (s, 4 H), 2.7 ppm (m, 1 H), 2.3 ppm (t, 2 H), 1.8 ppm (m, 2 H), 1.3 ppm ( m, 4H), 0.8 ppm (t, 3H). 2- [(Butylhydroxyphosphinyl) methyl] pentanedioic acid [2, 4-Di (benzyloxycarbonyl) -butyl] phosphinic acid (2.9 g, 6.5 mmol) in 30 mL of water containing 0.32 g 10% Pd / C was hydrogenated 40 psi for 4.5 hours. The mixture was filtered through a pad of Celite and evaporated under high vacuum to give 2- [(butylhydroxyphosphinyl) methyl] pentanedioic acid (4, R = n-butyl) (0.75 g, 43%) as a clear viscous oil and colorless. X H NMR (D 20): 2.4 ppm (m, 1 H), 2.1 ppm (t, 2 H), 1.9 ppm (m, 1 H), 1.6 ppm (m, 3 H), 1.4 ppm (m, 2 H), 1.1 ppm (m , 4H), 0.6 ppm (t, 3H). Elemental Analysis Calculated C10H19O6P, 0.5 H20: C, 43.64; H, 7.32. Found: C, 43.25; H, 7.12. EXAMPLE 3 Preparation of 2- [(Butylhydroxyphosphinyl) methyl] pentanedioic acid Scheme IV: R = CH2Ph, RX = H Osphinic benzyl acid Diethylchlorophosphite (25 g, 0.16 mol) was cooled in 100 Ml of dry diethyl ether at 0 ° C under one atmosphere of nitrogen. Benzylmagnesium chloride (80 Ml, 0.16 moles, 2.0 M solution in Et20) was added dropwise for two hours while maintaining a temperature below 10 ° C. A thick white suspension formed and stirring was continued at room temperature for 1 hour. The mixture was filtered under a nitrogen atmosphere and the filtrate was evaporated under reduced pressure to give a clear and colorless liquid. The liquid was stirred when 15 Ml of water was added followed by 0.5 ml of concentrated hydrochloric acid. An exothermic reaction was observed and stirring was continued for an additional 30 minutes followed by extraction with ethyl acetate. The organics were combined, washed with brine, dried (MgSO) and evaporated. Brilliant light golden liquid was added to the sodium hydroxide (50 Ml, 2.0 M NaOH), stirred for 1 hour and washed with diethyl ether. The aqueous layer was acidified to pH 1.0 with concentrated hydrochloric acid and extracted with ethyl acetate. The organics were combined, dried (MgSO4) and evaporated to give benzylphosphinic acid (1, R = CH2Ph, R? = H) (8 g, 32?;) as a bright light golden oil. LR NMR (dd DMSO): 7.3 ppm (m, 5H), 6.9 ppm (d, 1H), 3.1 ppm (d, 2H). Benzyl [2,4-di (benzyloxyarbonyl) butyl] phosphinic acid Benzylphosphinic acid (2.3 g, 15 mmol) was cooled in 150 mL of dry dichloromethane at 0 ° C under a nitrogen atmosphere. Triethylamine (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. After 30 minutes dibenzyl 2-methylene-pentanedioate (2) (4.4 g, 13.6 mmol) in 20 Ml of dichloromethane was added over 5 minutes. The reaction mixture was allowed to warm to room temperature and was 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 5% hydrochloric acid and with brine, dried (MgSO4) and evaporated to give a light yellow liquid. The purification by flash chromatography and elution with 1: 1 hexane / ethyl acetate containing 10% acetic acid yielded 2.0 g (28%) of benzyl [2,4-di (benzyloxycarbonyl) butyl] phosphinic acid (3, R = CH2Ph, R? = H) as a bright light yellow oil. Rf 0.37 (1: 1 Hexane / EtOAc, 10% AcOH). X H NMR (d 6 DMSO): 7.2 ppm (m, 15 H), 5.0 ppm (s, 4 H), 3.0 (d, 2 H), 2.8 ppm (m, 1 H), 2.3 ppm (t, 2 H), 1.9 ppm (m , 2H), 1.7 ppm (t, 1H). 2- [(Benzylhydroxyphosphinyl) methyl] pentanedioic acid Benzyl [2,4-dibenzyloxycarbonyl) butyl] -phosphinic acid (0.5 g, 1.0 mmol) was hydrogenated in 20 Ml of water containing 120 mg of 10 ?: Pd / C at 40 psi for 6 hours. Filtration through a pad of Celite followed by high vacuum evaporation gave 0.17 g (57%) of 2- [(benzylhydroxyphosphinyl) methyl] pentanedioic acid (4, R = CH Ph) as a white solid.

R NMR (D20): 7.1ppm (m, 5H), 2.9ppm (d, 2H), 2.4ppm '(m, 1H), 2.1ppm (t, 2H), 1.8ppm (m, 1H), 1.6ppm ( m, 3H). Elemental Analysis Calculated C13H? 706P: C, 52.00; H, 5.71. Found: C, 51.48; H, 5.70. EXAMPLE 4 Preparation of 2- [phenylethylhydrophosphinyl) -methyl] pentanedioic acid Scheme IV: R = CH2CH2Ph, R? = H Fenethylphosphinic acid Diethylchlorophosphite (15.6 g, 0.1 mol) was cooled in 100 Ml of dry diethyl ether at 5 ° C under a nitrogen atmosphere. Fenethylmagnesium chloride (100 Ml, 0.1 mol, 1.0 M in THF) was added dropwise for 2 hours while it was maintained at a temperature between 0-10 ° C. A thick white suspension was formed and stirred overnight at room temperature. The mixture was filtered under a nitrogen atmosphere and the filtrate was evaporated under reduced pressure to give a clear and colorless liquid. The liquid was stirred as 15 Ml water was added followed by 0.5 Ml of concentrated hydrochloric acid. An exothermic reaction was observed and stirring was continued for 15 minutes followed by extraction with ethyl acetate. The organics were combined, washed with brine, dried (MgSO4) and evaporated. The clear liquid was treated in sodium hydroxide (40 Ml, 2.0 M NaOH), stirred for 1 hour and washed once with diethyl ether. The aqueous layer was acidified to pH 1.0 with concentrated hydrochloric acid and extracted with ethyl acetate. The organics were combined, dried (MgSO) and evaporated to give the phenethylphosphinic acid (1, R = CH2CH2Ph, R? = H) (9.8 g, 58%) as a bright light yellow oil. 1 H NMR (d 6 DMSO): 7.2 ppm (m, 5H), 6.9 ppm (d, 1H), 2.8 ppm (m, 2H), 1.9 ppm (m, 2H). 2, 4-Di (benzyloxycarbonyl) butyl (phenethyl) phosphinic acid The phenethylphosphinic acid (1.0 g, 5.9 mmol) was cooled in 50 mL of dry dichloromethane at -5 ° C under a nitrogen atmosphere. Triethylamine (2.3 g, 23 mmol) was added followed by trimethylsilyl chloride (2.2 g, 21 mmol) while the reaction temperature was maintained at 0 ° C. After 10 minutes, dibenzyl 2-methylene-pentanedioate (2) (1-7 g, 5.2 mmol) in 10 Ml of dichloromethane was added over 10 minutes. The reaction mixture was allowed to warm to room temperature and stirred overnight . The clear solution was cooled to 0 ° C and quenched with 5% hydrochloric acid followed by the removal of the organic layer. The organic layer was washed with brine, dried (MgSO) and evaporated to give a bright golden light liquid. La by flash chromatography and elution with 1: 1 Hexane / EtOAc containing 5% AcOH yielded 1.2 g (41%) of 2,4-di (benzyloxycarbonyl) butyl (phenethyl) phosphinic acid (3, R = CH2CH2Ph, R ? = H) as a clear and colorless oil. ? R NMR (d6 DMSO): 7.2 ppm (m, 15H), 5.0 ppm (s, 4H), 3.3 ppm (m, 1H), 2.8 ppm (m, 4H), 2.3 ppm (m, 2H), 1.8 ppm (m, 4H). 2- (Phenethylhydroxyphosphinyl) methyl] pentanedioic acid 2,4,4-di (benzyloxycarbonyl) butyl (phenethyl) -phosphinic acid (1.1 g, 2.2 mmoles) in 20 Ml of water containing 120 mg of 10% Pd / C was hydrogenated during the night at 40 psi. Filtration through a pad of Celite followed by high vacuum evaporation gave 0.8 g (114%) of 2 - [(phenethylhydroxyphosphinyl) methyl] pentanedioic acid (4, R = CH2CH2Ph) as a white solid. lR NMR (D20): 7.2 ppm (m, 5H), 2.7 ppm (m, 2H), 2.5 ppm (m, 1H), 2.3 ppm (t, 2H), 1.9 ppm (m, 6H), 1.5 ppm (t , 1H) Elemental Analysis Calculated C ^ HigOeP, 0.75 H20, 0.5 AcOH ,: C, 50.35; H, 6.34. Found: C, 50.26; H, 5.78. EXAMPLE 5 Preparation of 2 - [(3-phenylpropylhydroxyphosphinyl) pentanedioic acid Scheme IV: R = CH2CH2CH2Ph, R? = H 3-Phenylpropylphosphinic acid By turning magnesium (2.44 g, 0.10 mol) into 20 Ml of dry diethyl ether under a Nitrogen atmosphere was added several iodine crystals. Phenylpropyl bromide (20.0 g, 0.10 mol) in 80 Ml of diethyl ether was placed in a dropping funnel. Approximately 10 Ml of the bromide solution was added by turning the magnesium and stirring was started. After several minutes the iodine was consumed and additional phenylpropyl bromide was added while maintaining a temperature of 35 ° C. Once the addition was complete (1.5 hours) the mixture was sealed and stored at 5 ° C. The diethylchlorophosphite (15.7 g, 0.1 mol) in 50 Ml of dry diethyl ether was cooled to 5 ° C under a nitrogen atmosphere. Fenethylmagnesium bromide (100 Ml, 0.1 mol, 1.0 M Et20 solution) was added dropwise for 2 hours while maintaining a temperature between 0-10 ° C. A thick white suspension formed and stirred for an additional 30 minutes. The mixture was filtered under a nitrogen atmosphere and the filtrate was evaporated under reduced pressure to give a clear and colorless liquid. 20 Ml was added to the water liquid followed by 0.5 ml of concentrated hydrochloric acid. An exothermic reaction was observed and stirring was continued for 20 minutes followed by extraction with ethyl acetate. The organics were combined, washed with brine, dried (MgSO4) and evaporated. Ae added sodium hydroxide to the clear liquid (40 Ml, 2.0 M NaOH), the resulting solution was stirred for 1 hour and then washed with diethyl ether. The aqueous layer was acidified to pH 1.0 with concentrated hydrochloric acid and extracted twice with ethyl acetate. The organics were combined, dried (MgSO4) and evaporated to give the 3-phenylpropylphosphinic acid (1, R = CH2CH2CH2Ph, R? = H) (9.8 g, 53%) as a clear and colorless oil. R NMR (d6 DMSO): 7.2 ppm (m, SH), 6.9 ppm (d, 1H), 2.6 ppm (t, 2H), 1.7 ppm (m, 2H), 1.6 ppm (m, 2H). 2, 4-Di (benzyloxycarbonyl) butyl (3-phenylpropyl) phosphinic acid 3-Phenylpropylphosphinic acid (1.0 g, 5.4 mmol) was cooled in 50 mL of dry dichloromethane at -5 ° C under a nitrogen atmosphere. Triethylamine (2.2 g, 22 mmol) was added followed by trimethylsilyl chloride (2.1 g, 19 mmol) while the reaction temperature was maintained at 0 ° C. After 10 minutes, dibenzyl 2-methylenediopenedioate (2) (1.6 g, 4.9 mmol) in 10 Ml of dichloromethane was added over 10 minutes. The reaction mixture was warmed to room temperature and dried. it stirred during the night. The clear solution was cooled to 0 ° C and quenched with 5% hydrochloric acid followed by the removal of the organic layer. The organic layer was washed with brine, dried (MgSO) and evaporated to give a light yellow liquid.

Purification by flash chromatography and elution with 4: 1 hexane / ethyl acetate containing 5% of the acetic acid result in 1.5 g (56%) of 2,4-di (benzyloxycarbonyl) -butyl (3-phenylpropyl) phosphinic acid (3, R = CH2CH2CH2Ph, R? = H) as a bright light yellow oil. Rf 0.58 (1: 1 Hexane / EtOAc, 5% AcOH). X H NMR (d 6 DMSO): 7.2 ppm (m, 15 H), 5.0 ppm (s, 4 H), 2.7 ppm (m, 1 H), 2.5 ppm (m, 5 H), 2.2 ppm (m, 2 H), 1.8 ppm ( m, 3H), 1.6 ppm (m, 2H). Elemental Analysis Calculated C 29 H 33 O 6 P, 1-3 H 20: C, 65.48; H 6.75. Found: C, 65.24; H, 6.39, 2- [(3-Phenylpropylhydroxyphosphinyl) methyl] pentanedioic acid 2,4-Di (benzyloxycarbonyl) butyl (3-phenylpropyl) phosphinic acid (15) was hydrogenated (1.4 g, 2.8 mmoles) in 20 Ml of water containing 150 mg of 10% Pd / C overnight at 40 psi Filtration through a pad of Celite followed by evaporation in high vacuum gave 0.8 g (89%) of acid 2- [(3-phenylpropylhydroxyphosphinyl) -methyl] pentanedioic acid (4, R = CH2CH2CH2Ph) as a bright yellow viscous oil.? RMN (D20): 7.4 ppm (m, SH), 2.7 ppm "(m, 3H), 2.4 ppm (t, 3H), 1.8 ppm (m, 7H). Elemental Analysis Calculated C? 5H? 06P, 0.75 H20, 0.75 AcOH ,: C, 51.23; H, 6.64. Found: C, 50.85; H, 6.02. EXAMPLE 6 Preparation of 2- [[(4-mebenzyl) hydroxy osphinyl] methyl] pentanedioic acid Scheme V: Compound 5, R = 4 methylbenzyl Hexamethyldisilazane (21.1 Ml, 100 mmol) was added to the vigorously stirred ammonium phosphinate (8.30 g. , 100 mmol), and the resulting suspension was stirred at 105 ° C for 2 hours. A solution of methylbenzyl 4-bromide (5.0 g, 27.0 mmol) was then added dropwise to the suspension at 0 ° C. The mixture was stirred at room temperature for 19 hours. The reaction mixture was then diluted with dichloromethane (50 Ml) and washed with 1 N HCl (50 Ml). The organic layer was separated, dried over Na2SO4, and concentrated to give 4.72 g of a white solid. This was dissolved in dichloromethane (50 Ml) and benzyl alcohol (3.24 g, 30 mmol) was added to the solution. Then 1,3-dicyclohexylcarbodiimide (DCC) (6.19 g, 30 mmol) was added to the solution at 0 ° C, and the suspension was stirred at room temperature for 14 hours. The solvent was removed under reduced pressure and the residue was suspended in EtOAc. The resulting suspension was filtered and the filtrate was concentrated. The residue was purified by silica gel chromatography (hexanes: EtOAc, 4: 1 to 1: 1) to give 2.40 g of 4-methylbenzyl-O-benzylphosphinic (2, R = 4 methylbenzyl) as a white solid (34% of performance). Rf 0.42 (EtOAc). XH NMR (DMSO-d6): d 2.30 (s, 3H), 3.29 (d, 2H), 5.2 (m, 2H), 7.0 (d, 1H), 7.1-7.2 (m, 4H), 7.3-7.4 ( m, 5H). 2,4-di (benzyloxycarbonyl) -butyl (4-methylbenzyl) -O-benzyl-osphinide acid was added to a solution of 4-methylbenzyl-O-benzylphosphinic acid (2, R = 4-methylbenzyl) (2.16 g, 8.3 mmol) ) in THF (15 Ml) sodium hydride (0.10 g, 60% dispersion in oil) followed by dibenzyl 2-methylene pentanodioate (3) (3.24 g) at 0 ° C, and the mixture was stirred at room temperature for 4 hours. The reaction mixture was then diluted with EtOAc (50 Ml) and poured into 1 N HCl (50 Ml). The organic layer was separated, dried over Na 2 SO, and concentrated.

This material was purified by silica gel chromatography (hexanes: EtOAc, 4: 1 to 1: 1) to give 3.41 g of 2,4-di (benzyloxycarbonyl) -butyl (4-methylbenzyl) -o-benzylphosphinic acid (4, R = 4-methylbenzyl) as a colorless oil (70% yield). Rf 0.61 (EtOAc). XH NMR (CDC13): d 1.6-1.8 (m, 1H), 1.9-2.0 (, 2H), 2.1-2.4 (m, 6H), 2.7-2.9 (m, 1H), 3.05 (dd, 2H), 4.8 -5.1 (m, 6H), 7.0-7.1 (m, 4H), 7.2-7.4 (m, 15H). 2- [[(4-Methylbenzyl) hydroxyphosphinyl] methyl] pentanedioic acid It was added to a solution of 2,4-di (benzyloxycarbonyl) butyl (4-methylbenzyl) -o-benzylphosphinic acid (0.70 g, 1.2 mmol) in ethanol (30 Ml) Pd / C (5%, 0.10 g) and the suspension was stirred under hydrogen (50 psi) for 18 hours. The suspension was then filtered through a pad of Celite and concentrated under reduced pressure. The resulting residue was dissolved in distilled water (5 Ml), passed through AG 50W X8 resin column (H + form), and lyophilized to give 0.21 g of 2 - [[(4-methylbenzyl) hydroxyphosphinyl] methyl] acid] pentanedioic acid (5, R = 4-methylbenzyl) as a white solid (55% yield). Rf 0. 62 (i-PrOH: H20, 7: 3). lH NMR (D? 0) d 1.7-1.9 (m, 3H), 2.0-2.2 (m, 1H), 2.33 (dt, 7.4 Hz, 2H), 2.55-2.70 (m, 1H), 3.12 (d, 2H ), 7.0-7.1 (m, 2H), 7.2-7.3 (m, 2H). Elemental Analysis Calculated C? 3H? 706P, 0.30 H20: C, 52.60; H, 6.18. Found: C, 52.60; H, 6.28. EXAMPLE 7 Preparation of the acid 2- [[(4-luorobenzyl) hydroxyphosphinyl] methyl] pentanedioic Scheme V: R = 4-fluorobenzyl. Prepared as described in the previous example where R = methylbenzyl. Rf 0.64 (i-PrOH: H20, 7: 3). LR NMR (D20): d 1.7-1.9 (m, 3H), 2.0-2.2 (m, 1H), 2.3-2.4 (m, 2H), 2.55-2.70 (m, 1H), 3.12 (d, 2H), 7.0-7.1 (m, 2H), 7.2-7.3 (m, 2H). Elemental Analysis Calculated C13H16F06P, 0.25 H20: C, 48.38; H, 5.15. Found: C, 48.38; H, 5.15. ? EXAMPLE 8 Preparation of the acid 2 - [[(4-methoxybenzyl) hydroxyphosphinyl] ethyl] pentanedioic Scheme V: R = -methoxybenzyl Prepared as described in the previous example where R = 4-methylbenzyl. Rf 0.56 (i-PrOH: H20, 7: 3). H NMR (D20): d 1.8-1.9 (m, 3H), 2.0-2.2 (m, 1H), 2.3-2.4 (m, 2H), 2.55-2.70 (m, 1H), 3.16 (d, 2H), 3.81 (s, 3H), 6.98 (d, 2H), 7.25 (d, 2H). Elemental Analysis Calculated C? 4H1907P, 0.30 H20: C, 50.09; H, 5.89. Found: C, '49.98; H, 5.80. EXAMPLE 9 Preparation of 2- [[(4-fluorobenzyl) hydroxyphosphinyl] methyl] pentanedioic acid Scheme V: R = 2-fluorobenzyl) Prepared as described in the previous example where R = methylbenzyl. Rf 0.6 7 (i-PrOH: H20, 7: 3). lR NMR (D20): d 1.8-1.9 (m, 3H), 2.0-2.2 (m, 1H), 2.3-2.4 (m, 2H), 2.55-2.70 (m, 1H), 3.28 (d, 2H), 7.1-7.5 (m, 4H). Elemental Analysis Calculated C? 3H16F06P, 0.10 H20,: C, 48.79; H, 5.10. Found: C, 48.84; H, 5.14. EXAMPLE 10 Preparation of 2 - [[(4-pentafluorobenzyl) hydroxy osphinyl] methyl] pentanedioic acid Scheme V: R = pentafluorobenzyl Prepared as described in the previous example where R = methylbenzyl. Rf 0.69 (i-PrOH: H20, 7: 3). XH NMR (D20): d 1.8-2.0 (m, 3H), 2.1-2.3 (m, 1H), 2.3-2.5 (m, 2H), 2.7-2.9 (m, 1H), 3.29 (d, 2H). Elemental Analysis Calculated C? 3H12F506P, 0.45 H20: C, 39.20; H, 3.26. Found: C, 39.17; H, 3.28. EXAMPLE 11 Preparation of 2- [(methylhydroxyphosphinyl) ethyl] pentanedioic acid Scheme VI. Compound 9 2,4-di (bensyloxycarbonyl) butylphosphinic acid (6) Ammonium phosphinate (10 g, 0.12 mole) was placed in a round bottom flask with stirring under a nitrogen atmosphere. Hexamethyldisilazane (HMDS), 25.5 Ml, 0.12 mol) was added and the mixture heated to 110 ° C. After two hours the mixture was cooled to 0 ° C and dichloromethane (120 ml) was added. After this was complete, dibenzyl-2-methylene 2-pentanedioate (41 g, 0.13 mol) was added dropwise. The mixture was allowed to warm to room temperature and was stirred for 16 hours. The mixture was then quenched with 5% HCl (75 ml) and the organic layer was stirred. The organics were dried (MgSO) and evaporated under reduced pressure to give 42 g (90%) of a clear and colorless oil. H NMR (CDC13): 7.36 ppm (m, 10H), 7.1 ppm (d, 1H), 5.19 ppm (s, 2H), 5.15 ppm (s, 2H), 2.92 ppm (m, 1H), 2.21 ppm (m , 6H). 2,4-Di- (benzyloxycarbonyl) butylbenzylphosphinic acid (7) Benzyl alcohol was added to a solution of 2,4-di (benzyloxycarbonyl) butyl-phosphinic acid (6) (19.3 g, 49.4 mmol) in tetrahydrofuran (5.3 g) , 49.3 mmoles) and dimethylamine pyridine (0.5 g). Dicyclohexylcarbodiimide (DCC, 12 g, 58 mmol) was added and a white precipitate formed. After 30 minutes the white suspension was filtered and the filtrate was evaporated under reduced pressure. The clear, colorless oil was purified by flash chromatography and eluted with 1: 1 Hexane / EtOAc to give 2,4-di (benzyloxycarbonyl) butylbenzylphosphinic acid (7) (11.5 g, 47%) as a clear and colorless oil. Rf 0.16 (1: 1 Hexane / EtOAc). XH NMR (CDC13): 7.3 ppm (m, 15H), 7.2ppm (d, 1H), 5.0ppm (m, 6H), 2.9ppm (m, 1H), 2.2ppm (m, 3H), 1.9ppm (m , 3H). 2, 4-Di- (benzyloxycarbonyl) butyl [hydroxy (phenyl) -methyl] benzylphosphinic acid (8) Acid 2 was added dropwise., 4-di (benzyloxycarbonyl) -butylbenzylphosphinic acid (7) in 5 Ml of dry THF at a cold stirring (0 ° C) the mixture of sodium hydride (0.09 g, 2.3 mmol) in 15 Ml of THF. After 15 minutes benzaldehyde (0.23 g, 2.2 mmol) was added by injection while maintaining a temperature of 0aC. After 30 minutes the mixture was quenched with water and extracted with two portions of dichloromethane. The organics were combined and evaporated to give a clear colorless oil. The oil was chromatographed on silica and eluted with a 1: 1 Hexane / EtOAc solvent system. The desired fractions were collected and evaporated to give 0.4 g (33%) of 2,4-di (benzyloxycarbonyl) butyl- [hydroxy (phenyl) methyl] benzylphosphinic acid (6) as a clear and colorless oil. Rf 0.18 (1: 1 Hexane / EtOAc). XH NMR (CDC13): 7.3 ppm (m, 20H), 5.2ppm (m, 1H), 4.9ppm (m, 6H), 2.8ppm (dm, 1H), 2.2ppm (m, 3H), 1.9ppm (m , 3H). 2- ([Hydroxy (phenyl) ethyl] hydroxyphosphinylmethyl) -pentanedioic acid (9) 2,4-Di- (benzyloxycarbonyl) butyl [hydroxy- (phenyl) methyl] benzylphosphinic acid (6) (0.37 g, 0.6 mmol) 25 Ml of water containing 0.10 g of 10% Pd / C was hydrogenated at 40 psi for 6 hours. The mixture was filtered through a pad of Celite and lyophilized to give 2- ([hydroxy (phenyl) methyl] hydroxyphosphini-1-methyl) pentanedioic acid (9) (0.14 g, 70%) as a white solid. LR NMR (D20): 7.4 ppm (m, 5H), 5.0 ppm (d, 1H), 2.7 ppm (m, 1H), 2.4 ppm (m, 2H), 2.2 ppm (m, 1H), 1.9 ppm (m , 3H). Elemental analysis: Calculated C13H? 707P, 0.6 H20: C, 47.74; H, 5.61. Found: C, 47.73; H, 5.68. EXAMPLE 12 Preparation of dibenzyl 2-methylene pentanedioate using Scheme III. Benzyl acrylate (500 g, 3.0 mol) was heated in an oil bath at 100 ° C. The heating was stopped and HMPT (10 g, 61 mmol) was added by dripping while maintaining an internal temperature below 140 ° C. Once the addition was complete, the mixture was stirred and cooled to room temperature. A suspension of silica (5: 1 Hexane / EtOAc) was added and the mixture was placed on a column containing a dry silica plug. The column was washed with 1: 1 Hexane / EtOAc and the fragments were combined and evaporated to give 450 g of the bright golden light liquid. The liquid was distilled under high vacuum (200 μHg) at 185 ° C to give 212 g (42%) of a clear and colorless liquid. XH NMR (CDC13): 7.3 ppm (m, 10H), 6.2 ppm (s, 1H), 5.6 ppm (s, 1H), 5.2 ppm (s, 2H), 5.1 ppm (s, 2H), 2.6 ppm (m , 4H). EXAMPLE 13 Preparation of 2- [[bis (benzyloxy) phosphoryl] methyl] pon dibenzyl andioate using Scheme III Dibenzylphosphite (9.5 g, 36 mmol) was cooled in 350 ml of dichloromethane at 0 ° C. To this stirred solution was added trimethyl aluminum (18.2 ml, 2.0 M hexane solution, 36.4 mmoles). After 30 minutes, dibenzyl 2-methylenediopentadioate (2) (6.0 g, 37 mmol) in 90 ml of dichloromethane was added dropwise over 10 minutes. The clear and colorless solution was then warmed to room temperature and allowed to stir overnight. The mixture was then quenched by the slow addition of 5% HCl. After stirring an additional 1.5 hours, the lower organic layer was removed and the aqueous layer was extracted once with 100 ml of dichloromethane. The organics were combined, dried (MgSO4), and evaporated to give a bright golden light liquid. The liquid was taken on silica gel chromatography (4cm * 30cm) and eluted with a solvent system (4: 1-1: 1) of gradient (Hexane / EtOAc). The fractions containing the desired product were combined and evaporated to give dibenzyl 2- [[bis (benzyloxy) -phosphoryl] methyl] pentanedioate (7.1 g, 42%) as a clear and colorless liquid. The liquid was then distilled in a Kughleror apparatus at 0.5 mm Hg and 195-200 ° C. The distillate was discarded and the rest of the bright golden oil was chromatographed on silica gel (1: 1, Hexane / EtOAc) to give 2.9 g of dibenzyl 2- [[bis (benzyloxy) phosphoryl] methyl] pentanedioate as an oil clear and colorless. TLC Rf 0.5 (1: 1 Hexane / EtOAc). lR NMR (CDC13): 7.1-7.4 (m, 20H), 5.05 (s, 2H), 4.8-5.03 (m, 6H), 2.8 (1H), 2.22-2.40 (m, 3H), 1.80-2.02 (m , 3H). EXAMPLE 14 Preparation of 2- (phosphonomethyl] pentanedioic acid (Compound 3) using Scheme III Benzyl pentanedioate 2 (2.9 g, 4.9 mmol) was added to a mixture of 20 ml of methanol containing 0.29 g (6 mol%) 10% Pd / C This mixture was hydrogenated at 40 psi for 24 hours, filtered and evaporated to give 3 (1.0 g, 90%) as a slightly light golden viscous oil XH NMR (D20): 2.6-2.78 (m, 1H), 2.25-2.40 (m, 2H), 1.75-2.15 (m, 4H) EXAMPLE 15 A patient is at risk of injury from an ischemic case.The patient can be pretreated with an effective amount of a compound or a pharmaceutical composition of the present invention It is expected that after the pretreatment, the patient can be protected from any injury due to the ischemic case EXAMPLE 16 A patient suffering from an ischemic case.

The patient may be administered during or after the case, an effective amount of a compound or a pharmaceutical composition of the present invention. It is expected that after the treatment, the patient can recover or not suffer any major injury due to the ischemic case. EXAMPLE 17 A patient who has suffered an ischemic case injury. The patient can be administered an effective amount of a compound or a pharmaceutical composition of the present invention. It is expected that after the treatment, the patient can recover from the injury due to the ischemic case. EXAMPLE 18 A patient who is suffering from a glutamate abnormality. The patient can then be administered an effective amount of a compound or a pharmaceutical composition of the present invention. It is expected that after treatment, the patient may be protected from further injury due to the glutamate abnormality or may recover from the glutamate abnormality. EXAMPLE 19 A patient who is suffering or has suffered a nervous attack, such as that arising from a neurodegenerative disease or a neurodegenerative process. The patient can then be administered an effective amount of a compound or a pharmaceutical composition of the present invention. It is expected that after treatment, the patient can protect himself from further injury due to nervous attack or can recover from nervous attack. EXAMPLE 20 A patient who is suffering from Parkinson's disease. The patient can be administered an effective amount of a compound or a pharmaceutical composition of the present invention. It is expected that after treatment, the patient can be protected from further neurodegeneration or be able to recover from Parkinson's disease. EXAMPLE 21 A patient who is suffering from ALS. The patient can then be administered an effective amount of a compound or a pharmaceutical composition of the present invention. It is expected that after treatment, the patient can be protected from further neurodegeneration or be able to recover from ALS.

EXAMPLE 22 A patient who is suffering from epilepsy. The patient can then be administered an effective amount of a compound or a pharmaceutical composition of the present invention. It is expected that after treatment, the patient can be protected from further neurodegeneration or be able to recover from epilepsy. EXAMPLE 23 A patient who is suffering from abnormalities in myelination / demyelination processes. The patient can then be administered an effective amount of a compound or a pharmaceutical composition of the present invention. It is expected that after treatment, the patient can be protected from further neurodegeneration or be able to recover from abnormalities in myelination / demyelination processes. EXAMPLE 24 A patient who is suffering or has. suffered a stroke, such as an attack. The patient can then be administered an effective amount of a compound or a pharmaceutical composition of the present invention. It is expected that after treatment, the patient can protect himself from or be able to recover from any injury due to the stroke.

EXAMPLE 25 A patient who is suffering from a head trauma. The patient can then be administered an effective amount of a compound or a pharmaceutical composition of the present invention. It is expected that after treatment, the patient can protect himself from or be able to recover from any cerebro spinal or peripheral ischemic injury, which is the result of the head trauma. EXAMPLE 26 A patient who is suffering from spinal trauma.

The patient can then be administered an effective amount of a compound or a pharmaceutical composition of the present invention. It is expected that after treatment, the patient can protect himself from or be able to recover from any ischemic injury that is the result of spinal trauma. ? JEMPLO 27 A patient is about to undergo surgery. The patient can be administered an effective amount of a compound or a pharmaceutical composition of the present invention. It is expected that after treatment, the patient will not be able to develop any spinal or peripheral ischemic head injury that results from or associated with surgery. JMPLO 28 A patient who is suffering from focal ischemia, such as that associated with thromboembolic occlusion of a cerebral vessel, traumatic head injury, edema or brain tumors. The patient can then be administered an effective amount of a compound or a pharmaceutical composition of the present invention. It is expected that after the treatment, the patient can protect himself from or be able to recover from any spinal or peripheral cerebral injury, which is the result of focal ischemia. ? JEMPLO 29 A patient who is suffering from global ischemia. The patient can then be administered an effective amount of a compound or a pharmaceutical composition of the present invention. It is expected that after treatment, the patient can protect himself from or be able to recover from any brain, spinal or peripheral injury that is the result of global ischemia. JMPLO 30 A patient who is suffering from a heart attack. The patient can then be administered an effective amount of a compound or a pharmaceutical composition of the present invention. It is expected that after treatment, the patient can protect himself from or be able to recover from any cerebral, spinal or peripheral ischemic injury associated with the heart attack. JMPLO 31 A patient who is suffering from hypoxia, asphyxia or perinatal asphyxia. The patient can then be administered an effective amount of a compound or a pharmaceutical composition of the present invention. It is expected that after treatment, the patient can protect himself from or recover from any ischemic, spinal or peripheral injury associated with hypoxia, asphyxia or perinatal asphyxia. EXAMPLE 32 A patient who is suffering from a brain-cortical injury. The patient can then be administered an effective amount of a compound or a pharmaceutical composition of the present invention. It is expected that after treatment, the patient can protect himself from or be able to recover from any ischemic brain injury that is the result of the brain-cortical injury. EXAMPLE 33 The patient is suffering an injury to the caudate nucleus. The patient can then be administered an effective amount of a compound or a pharmaceutical composition of the present invention. It is expected that after the treatment, the patient can protect himself from or be able to recover from any ischemic brain injury that is the result of injury to the caudate nucleus. EXAMPLE 34 A patient suffering from a cortical lesion due to a condition identified in these examples. The patient can then be administered an effective amount of a compound or a pharmaceutical composition of the present invention. It is expected that after treatment, the patient may be protected from further injury, or may exhibit at least 65% to at least 80% recovery of the cortical lesion. EXAMPLE 35 A patient suffering from multiple sclerosis. The patient can then be administered an effective amount of a compound or a pharmaceutical composition of the present invention. It is expected that after treatment, the patient can be protected from further demyelination or be able to recover from multiple sclerosis. EXAMPLE 36 A patient who is suffering from a peripheral neuropathy caused by Guillain-Barré syndrome. The patient can then be administered an effective amount of a compound or a pharmaceutical composition of the present invention. It is expected that after treatment, the patient can be protected from further demyelination or be able to recover from peripheral neuropathy. EXAMPLE 37 The patient is suffering from alcoholism. The patient can then be administered an effective amount of a compound or a pharmaceutical composition of the present invention. It is expected that after the treatment, that the patient's desire for alcohol can be suppressed. EXAMPLE 38 A patient who is suffering from nicotine dependence. The patient can then be administered an effective amount of a compound or a pharmaceutical composition of the present invention. It is expected that after the treatment, that of the patient's desire for nicotine can be suppressed. EXAMPLE 39 The patient is suffering from cocaine dependence. The patient can then be administered an effective amount of a compound or a pharmaceutical composition of the present invention. It is expected that after the treatment, the patient's desire for cocaine can be suppressed. ? JEMPLO 40 A patient who is suffering from heroin dependence. The patient can then be administered an effective amount of a compound or a pharmaceutical composition of the present invention. It is expected that after the treatment, the patient's desire for heroin can be suppressed. EXAMPLE 41 The patient is suffering from compulsive overeating, obesity or severe obesity. The patient can then be administered an effective amount of a compound or a pharmaceutical composition of the present invention. It is expected that after the treatment the patient's compulsion to eat can be suppressed. EXAMPLE 42 A patient who is suffering from pathological gambling.

The patient can then be administered an effective amount of a compound or a pharmaceutical composition of the present invention. It is expected that after the treatment, the patient's compulsion to play can be suppressed. EXAMPLE 43 The patient is suffering from ADD. The patient can then be administered an effective amount of a compound or a pharmaceutical composition of the present invention. It is expected that after the treatment, the symptoms of the patient Í80 lack of attention, impulsivity and / or hyperactivity can be suppressed. EXAMPLE 44 A patient who is suffering from Tourette's syndrome. The patient can then be administered an effective amount of a compound or a pharmaceutical composition of the present invention. It is expected that after the treatment, simple, complex, vocal and respiratory nervous contractions of the patient can be suppressed. EXAMPLE 45 A patient suffering from adenocarcinoma of the prostate. The patient can then be administered an effective amount of a compound or a pharmaceutical composition of the present invention. After this initial treatment, the patient may optionally be administered the same or a different compound of the present invention in continuous or intermediate continuous doses per subdural pump. It is expected that the treatment (s) may prevent the recurrences of the adenocarcinoma, or inhibit (ie, develop the attack) or alleviate (i.e., cause the regression of) the adenocarcinoma tumor cells. EXAMPLE 46 A patient who is suffering from adenocarcinoma of the prostate. The patient can then be administered an effective amount of a compound or a pharmaceutical composition of the present invention by direct injection into the tumor. After this initial treatment, the patient may be administered an optionally effective amount thereof or a different compound of the present invention in intermittent or continuous doses by implantation of a biocompatible polymer matrix delivery system. It is expected that the treatment (s) may prevent recurrences of adenocarcinoma, inhibit (ie, attack to the development of) or relieve (ie, cause regression of) adenocarcinoma tumor cells. EXAMPLE 47 A patient is diagnosed with benign prostatic hyperplasia. The patient can then be administered an effective amount of a compound or a pharmaceutical composition of the present invention by direct injection into the tumor. After this initial treatment, the patient can optionally be administered the same or a different compound of the present invention in intermittent or continuous doses by injection, subdural pump or polymeric matrix graft. It is expected that after the treatment or treatments, benign prosthetic hyperplastic cells can not develop in the carcinoma.

JMPLO 48 A patient who is suffering from adenocarcinoma of the prostate. The adenocarcinoma does not seem to have increased metastasis. The patient who. undergo surgery to remove adenocarcinoma. After recovery from post-surgery, the patient can be administered an effective amount of a compound or a pharmaceutical composition of the present invention locally in intermittent or continuous doses by injection, subdural pump or polymeric matrix graft. It is expected that after treatment, the patient can be protected from recurrences of adenocarcinoma, and any residual tumor cells can be inhibited (ie, developing attack) or relieved (i.e., caused by backing off). JMPLO 49 A patient who is suffering from metastatic adenocarcinoma of the prostate. Although the adenocarcinoma seems to have increased metastasis, the patient undergoes surgery nevertheless to remove the adenocarcinoma. The patient can then be locally administered an effective amount of a compound or a pharmaceutical composition of the present invention from the time of initial diagnosis through postsurgical recovery. After the postsurgical recovery, the patient can continue the same treatment by a periodic local administration regimen, and carefully monitor for adverse side effects. It is expected that after the treatments, the patient can be protected from the recurrences of the adenocarcinoma, and any residual tumor cells can be inhibited (ie, developing attack) or relieved (ie, caused to regress). EXAMPLE 50 A patient is suffering from cancer as defined herein. An effective amount of a compound or a pharmaceutical composition of the present invention can be administered directly to cancer cells. After this treatment is initiated, the patient can be administered an optionally effective amount thereof or a different compound of the present invention by direct injection, subdural bobeo or implantation of a biocompatible polymer matrix delivery system. It is expected that after the treatment (s), the patient can protect himself / herself from cancer recurrences, and the cancer will be inhibited (ie developing attack) or relieved (ie, caused by backing off). EXAMPLE 51 A patient is diagnosed with a disease, disorder or condition as identified in these examples.

An effective amount of a compound or a pharmaceutical composition of the present invention can then be administered intravenously to the patient, intramuscularly, intraventricularly to the brain, rectal, hypodermic, intranasally, through a catheter with or without a pump, orally, through a transdermal patch, topically, or through a polymer graft. The patient's condition can be expected to improve after treatment. ? JEMPLO 52 A patient is diagnosed with a disease, disorder or condition as identified in these examples. A compound or a pharmaceutical composition of the present invention can then be administered to the patient in the form of a bolus of 100 mg / kg, optionally followed by an intravenous infusion of 20 mg / kg per hour for a period of time of two hours. It can be expected that the patient's condition improves after treatment. The invention being in this described manner, it will be obvious for it to be varied in many ways. The variations will not be considered as a departure from the spirit and scope of the invention and all modifications are intended to be included within the scope of the following claims.

Claims (83)

R? IVINDICATION? 1. A prodrug of a NAALADase inhibitor. 2. The prodrug according to claim 1, characterized in that the NAALADase inhibitor is a hydroxyphosphinyl derivative of glutamate derived from the formula I: or a pharmaceutically acceptable salt or hydrate thereof, wherein: X is CR3R4, 0 or NR5; Ri and R5 are independently selected from the group consisting of hydrogen, straight or branched chain C1-C9 alkyl, straight or branched chain C2-Cg alkenyl, C3-C8 cycloalkyl, C5-C7 cycloalkenyl and Ar, wherein such Ri and Rs are independently unsubstituted or substituted with one or more substituents independently selected from the group consisting of carboxy, C3-Cs cycloalkyl, C5-C7 cycloalkenyl, halo, hydroxy, nitro, trifluoromethyl, Ci-Cc alkyl straight or branched chain, straight or branched chain C2-C6 alkenyl, C1-C9 alkoxy, C2-Cg alkenyloxy, phenoxy, benzyloxy, amino, and Ar; R3 and R4 are independently selected from the group consisting of hydrogen, straight or branched chain C6-C6 alkyl, straight or branched chain C2-Cg alkenyl, C3-Cg cycloalkyl, Cs-C cycloalkenyl, Ar, and halo; . R2 are selected from the group consisting of hydrogen, straight or branched chain C1-C9 alkyl, straight or branched chain C2-Cg alkenylene, C3-C8 cycloalkyl, C5-C7 cycloalkenyl and Ar, wherein such R2 is substituted or unsubstituted with one or more substituents independently selected from the group consisting of carboxy, C3-C8 cycloalkyl, C5-C7 cycloalkenyl, halo, hydroxy, nitro, trifluoromethyl, straight or branched chain Ci-Cs alkyl, straight or branched chain C2-C6 alkenyl, Ci-Cß alkoxy, C2-Ce alkenyloxy, phenoxy, benzyloxy, amino, and Ar; 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 substituted or unsubstituted with one or more substituents independently selected from the group consisting of carboxy, halo, hydroxy, nitro, trifluoromethyl, Ci-Cβ alkyl straight or branched chain, straight or branched chain C2-Cd alkylene, Ci-Cβ alkoxy, C? -Cs alkenyloxy, phenoxy, benzyloxy, and amino. 3. The prodrug according to claim 2, characterized in that X is CH2. 4. The prodrug according to claim 3, characterized in that R2 is substituted with carboxy. 5. The prodrug according to claim 4, characterized in that: R1 is hydrogen, straight or branched chain C5.-C4 alkyl, straight or branched chain C2-C4 alkenyl, C3-C8 cycloalkenyl cycloalkenyl of C5- C7, benzyl or phenyl, wherein Ri is substituted or unsubstituted with one or more substituents independently selected from the group consisting of carboxy, C3-CB cycloalkyl, Cs-C7 cycloalkenyl, halo, hydroxy, nitro, trifluoromethyl, Straight or branched chain C? -C6, straight or branched chain C2-C6 alkenyl, C? -C4 alkoxy / C2-C alkenyloxy, phenoxy, benzyloxy, amino, benzyl, and phenyl; and 2 is C1-C2-6 alkyl. The prodrug according to claim 5, characterized in that the derivatized hydroxyphosphinyl derivative of glutamate is selected from the group consisting of: 2- (phosphonomethyl) pentanedioic acid; 2- (phosphonomethyl) succinic acid; 2- [[(2-carboxyethyl) hydroxyphosphinyl] methyl] pentanedioic acid; 2- [(benzylhydroxyphosphinyl) methylpentanedioic acid; 2- [(phenylhydroxyphosphinyl) methyl] pentanedioic acid; 2- [[((Hydroxy) phenylmethyl) hydroxyphosphinyl] methyl] pentanedioic acid; 2- [(butylhydroxyphosphinyl) methyl] pentanedioic acid; 2- [[(3-methylbenzyl) hydroxyphosphinyl] methyl] pentanedioic acid; 2- [(3-phenylpropylhydroxyphosphinyl) methyl] pentanedioic acid; 2 - [[(4-fluorophenyl) hydroxyphosphinylmethyl] pentanedioic acid; 2- [(Methylhydroxyphosphinyl) methyl] pentanedioic acid; 2- (phenylethylhydroxyphosphinyl) methyl] pentanedioic acid; 2 - [[(4-methylbenzyl) hydroxyphosphinyl] methyl] pentanedioic acid; 2- [[(4-fluorobenzyl) hydroxyphosphinyl] methylpentanedioic acid; 2- [[(4-methoxybenzyl) hydroxyphosphinyl] methyl] pentanedioic acid; 2- [[3-trifluoromethylbenzyl] hydroxyphosphinyl] methyl] pentanedioic acid; acid - [[(2-fluorobenzyl) hydroxyphosphinyl] methyl] pentanedioic acid; 2- [[(pentafluorobenzyl) hydroxyphosphinyl] methyl] pentanedioic acid; 2- [(Phenylpro-2-enyl) hydroxyphosphinyl] methyl] pentanedioic acid; 2- [(aminomethyl) hydroxyphosphinyl] methyl] pentanedioic acid; 2- [(Aminoethyl) hydroxyphosphinyl] methyl] pentanedioic acid 2- [[(aminopropyl) hydroxyphosphinyl] methyl] pentanedioic acid; and pharmaceutically acceptable salts and hydrates thereof. The prodrug according to claim 6, characterized in that the derivatives of dihydroxyphosphinyl glutamate derivative is 2- (phosphonomethyl) pentanedioic acid or a pharmaceutically acceptable salt or hydrate thereof. 8. A compound of formula II or a pharmaceutically acceptable salt or hydrate thereof, characterized in that: X is CR5R6, NR7 or O; Ri and R7 are independently selected from the group consisting of hydrogen, straight or branched chain Ci-Cg alkyl, straight or branched chain C2-Cg alkenyl, C3-Cs cycloalkyl, C5-C7 cycloalkenyl and Ari, wherein such Ri and R7 are independently unsubstituted or substituted with one or more substituents independently selected from the group consisting of carboxy, C3-C8 cycloalkyl, C5-C7 cycloalkenyl, halo, hydroxy, nitro, trifluoromethyl, Ci-Cc alkyl straight or branched chain, straight or branched chain C2-C2 alkenyl, C1-C9 alkoxy, C? -9 alkenyloxy, phenoxy, benzyloxy, amino, and Ar ?; R2 is selected from the group consisting of hydrogen, straight or branched chain C1-C9 alkyl, straight or branched chain C? -Cg alkenyl, C3-C8 cycloalkyl, C5-C7 cycloalkenyl and Ari, wherein R? is substituted or unsubstituted with one or more substituents independently selected from the group consisting of carboxy, C3-C8 cycloalkyl, C5-C7 cycloalkenyl, halo, hydroxy, nitro, trifluoromethyl, straight or branched chain Ci-Cs alkyl, straight or branched chain C2-C6 alkenyl, Ci-Cß alkoxy, C2-Ce alkenyloxy, phenoxy, benzyloxy, amino, and Ar2; R3 and R4 are independently selected from the group consisting of hydrogen, carboxy, straight or branched chain C1-C9 alkyl, straight or branched chain C2-Cg alkenyl, C3-C3 cycloalkyl, C ^ -CT cycloalkenyl, and Ar, with the proviso that both R3 and R4 are not hydrogen; wherein such R3 and R4 are independently unsubstituted or substituted with one or more substituents independently selected from the group consisting of carboxy, C3-C3 cycloalkyl, C5-C7 cycloalkenyl, halo, hydroxy, nitro, trifluoromethyl, Ci-alkyl Straight or branched chain Cs, straight or branched chain C2-C6 alkenyl, C6-6 alkoxy, C6-6 alkenyloxy, phenoxy, benzyloxy, amino, and Ar2; R5 and Re are independently selected from the group consisting of hydrogen, straight or branched chain Ci-Cß alkyl, straight or branched chain C2-Cd alkenyl, C3-C8 cycloalkyl, C5-C7 cycloalkenyl, Ari, and halo; Ari and Ar2 are independently 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 such Ari and Ar2 are independently unsubstituted or substituted with one or more substituents independently selected from the group consisting of halo, hydroxy, nitro, trifluoromethyl, alkyl of straight or branched chain Ci-Cß, straight or branched chain C2-C6 alkenyl, Ci-Ce alkoxy, C2-C6 alkenyloxy, phenoxy, benzyloxy, and amino. 9. The compound according to claim 8, characterized in that: R4 is hydrogen; and R 3 is substituted with one or more substituents independently selected from the group consisting of carboxy, Ci-Cβ alkoxy, C?-Cg alkenyloxy, phenoxy, and benzyloxy. The compound according to claim 9, characterized in that it is selected from the group consisting of: 2- [(benzylmethoxyphosphinyl) methyl] pentanedioic acid; 2- [(benzyloxyethoxyphosphyl) methyl] pentanedioic acid; 2- [(benzylpropoxyphosphinyl) methyl] pentanedioic acid; 2- [(benzylacetoxyphosphyl) methyl] pentanedioic acid; 2- [(benzylbenzyloxyphosphinyl) methyl] pentanedioic acid; 2- [(Benzyl (1-oxopropoxy) methoxyphosphinyl) methyl] pentanedioic acid; 2- [(pentafluorobenzylmethoxyphosphinyl) methyl pentanedioic acid; 2- [(pentafluorobenzyl-ethoxy-phosphinyl) -methyl] -pentanedioic acid; 2- [(pentafluorobenzylopropoxyphosphinyl) methyl] pentanedioic acid; 2- [(pentafluorobenzylcoxethoxyphosphinyl) methyl] pentanedioic acid; 2- [(pentafluorobenzyl (1-oxo-propoxy) phosphinyl) methyl] pentandioic; and the pharmaceutically acceptable salts and hydrates thereof. 11. A method for treating an abnormality of glutamate in an animal, characterized in that it comprises administering an effective amount of a prodrug of a NAALADase inhibitor to said animal. The method according to claim 11, characterized in that the prodrug is administered in combination with at least one additional therapeutic agent. 13. The method according to the claim 11, characterized in that the glutamate abnormality is selected from the group consisting of epilepsy, stroke, Alzheimer's disease, Parkinson's disease, Amyotrophic Lateral Sclerosis (ALS), Huntington's disease, schizophrenia, chronic pain, ischemia, peripheral neuropathy, traumatic injury cerebral and physical damage to the spinal cord. 14. The method according to claim 13, characterized in that the glutamate abnormality is ischemia. 15. The method according to claim 13, characterized in that the glutamate abnormality is apoplexy. 16. The method according to claim 13, characterized in that the glutamate abnormality is the Parkinson's disease 17. The method according to claim 13, characterized in that the abnormality of glutamate is Amyotrophic Lateral Sclerosis (ALS). 18. The method according to claim 13, characterized in that the glutamate abnormality is the ischemic spinal cord injury. 19. The method according to claim 11, characterized in that the NAALADase inhibitor is a glutamate derived from hydroxyphosphinyl derivative of the formula I: or a pharmaceutically acceptable salt or hydrate thereof, wherein: X is CR3R4, 0 or NR5; Ri and R5 are independently selected from the group consisting of hydrogen, straight or branched chain C? -Cg alkyl, straight or branched chain C2-Cg alkenyl, C3-C8 cycloalkyl C5-C7 cycloalkenyl and Ar, in wherein such Ri and R5 are independently unsubstituted or substituted with one or more substituents independently selected from the group consisting of carboxy, C3-C8 cycloalkyl, C5-C7 cycloalkenyl, halo, hydroxy, nitro, tri? luoromethyl, Ci alkyl Straight chain or branched chain, straight or branched chain C2-C6 alkenyl, Ci-Cg alkoxy, C¿-C9 alkenyloxy, phenoxy, benzyloxy, amino, and Ar; R3 and R4 are independently selected from the group consisting of hydrogen, straight or branched chain Ci-Ce alkyl, straight or branched chain C2-C6 alkenyl, C3-C8 cycloalkyl, C5-C7 cycloalkenyl, Ar, and halo; R? are selected from the group consisting of hydrogen, straight or branched chain C1-C9 alkyl, straight or branched chain C2-Cg alkenylene, C3-C8 cycloalkyl, C5-C7 cycloalkenyl and Ar, wherein such R2 is substituted or unsubstituted with one or more substituents independently selected from the group consisting of carboxy, C3-C8 cycloalkyl, C5-C7 cycloalkenyl, halo, hydroxy, nitro, trifluoromethyl, straight or branched chain Ci-Ce alkyl, alkenyl of C2-C6 straight or branched chain, C? -C6 alkoxy, C2-C6 alkenyloxy, phenoxy, benzyloxy, amino, and Ar; 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, in that such Ar is substituted or unsubstituted with one or more substituents independently selected from the group consisting of carboxy, halo, hydroxy, nitro, trifluoromethyl, straight or branched chain C 1 -C 6 alkyl, straight chain C 2 -C 6 alkylene or branched, Ci-Cβ alkoxy, C2-C6 alkenyloxy, phenoxy, benzyloxy, and amino. 20. The method of compliance with the claim 19, characterized in that X is CH2. 21. The method according to the claim 20, characterized in that R2 is substituted with carboxy. 22. The method according to claim 21, characterized in that: R1 is hydrogen, straight or branched chain C?-C4 alkyl, straight or branched chain C2-C4 alkenyl, C3-C8 cycloalkyl, C0 cycloalkenyl -C7, benzyl or phenyl, wherein Ri is substituted or unsubstituted with one or more substituents independently selected from the group consisting of carboxy, C3-C8 cycloalkyl, C5-C7 cycloalkenyl, halo, hydroxy, nitro, trifluoromethyl, straight or branched chain C 1 -C 6 alkyl, straight or branched chain C 2 -C 6 alkenyl, C 1 -C 4 alkoxy, C 2 -C 4 alkenyloxy, phenoxy, benzyloxy, amino, benzyl, and phenyl; and R2 is C? -C2 alkyl. The method according to claim 22, characterized in that the derivatized hydroxyphosphinyl derivative of glutamate is selected from the group consisting of: 2- (phosphonomethyl) pentanedioic acid; 2- (phosphonomethyl) succinic acid; 2- [[(2-carboxyethyl) hydroxyphosphinyl] methyl] pentanedioic acid; 2- [(benzylhydroxyphosphinyl) methylpentanedioic acid; 2- [(phenylhydroxyphosphinyl) methyl] pentanedioic acid; 2- [[((Hydroxy) phenylmethyl) hydroxyphosphinyl] methyl] pentanedioic acid; 2- [(butylhydroxyphosphinyl) methyl] pentanedioic acid; 2 - [[(3-methylbenzyl) hydroxyphosphinyl] methyl] pentanedioic acid; 2- [(3-phenylpropylhydroxyphosphinyl) methyl] pentanedioic acid 2 - [[(4-fluorophenyl) hydroxyphosphinylmethyl] pentanedioic acid; 2- [(Methylhydroxyphosphinyl) methyl] pentanedioic acid; 2- (phenylethylhydroxyphosphinyl) methyl] pentanedioic acid; 2 - [[(4-methylbenzyl) hydroxyphosphinyl] methyl] pentanedioic acid; 2 - [[(4-fluorobenzyl) hydroxyphosphinyl] methylpentanedioic acid; 2 - [[(4-methoxybenzyl) hydroxyphosphinyl] methyl] entanedioic acid; 2 - [[3-trifluoromethylbenzyl] hydroxyphosphinyl] methyl] pentanedioic acid; 2- [[(2-fluorobenzyl) hydroxyphosphinyl] methyl] pentanedioic acid; 2- [[(pentafluorobenzyl) hydroxyphosphinyl] methyl] pentanedioic acid; 2- [(Phenylpro-2-enyl) hydroxyphosphinyl] methyl] pentanedioic acid; 2- [(aminomethyl) hydroxyphosphinyl] methyl] pentanedioic acid; "2- [(aminoethyl) hydroxyphosphinyl] methyl] pentanedioic acid 2- [[(aminopropyl) hydroxyphosphinyl] methyl] pentanedioic acid; and pharmaceutically acceptable salts and hydrates thereof 24. The method according to claim 23, characterized because the derivatized hydroxyphosphinyl glutamate derivative is 2- (phosphonomethyl) pentanedioic acid or a pharmaceutically acceptable salt or hydrate thereof 25. The method according to claim 11, characterized in that the prodrug is a compound of the formula II or a pharmaceutically acceptable salt or hydrate thereof, wherein: X is CR5R6, NR7 or O; Ri and R7 are independently selected from the group consisting of hydrogen, straight or branched chain C1-C9 alkyl, straight or branched chain C2-C9 alkenyl, C-C8 cycloalkyl, C5-C7 cycloalkenyl and Ari, wherein such Ri and R7 are independently unsubstituted or substituted with one or more substituents independently selected from the group consisting of carboxy, C3-C8 cycloalkyl, C5-C7 cycloalkenyl, halo, hydroxy, nitro, trifluoromethyl, C? C & straight or branched chain, straight or branched chain C2-Cd alkenyl, C1-C9 alkoxy, C2-C9 alkenyloxy, phenoxy, benzyloxy, amino, and Ar ?; R2 is selected from the group consisting of hydrogen, straight or branched chain C1-C9 alkyl, straight or branched chain C? -Cg alkenyl, C3-C8 cycloalkyl, C5-C7 cycloalkenyl and Ari, wherein R2 is substituted or unsubstituted with one or more substituents independently selected from the group consisting of carboxy, C3-C8 cycloalkyl, C5-C7 cycloalkenyl, halo, hydroxy, nitro, trifluoromethyl, straight or branched chain Ci-Cs alkyl , straight or branched chain C2-C6 alkenyl, Ci-Ce alkoxy, C2-C6 alkenyloxy, phenoxy, benzyloxy, amino, and Ar2; R3 and R are independently selected from the group consisting of hydrogen, carboxy, straight or branched chain C1-C9 alkyl, straight or branched chain C2-Cg alkenyl, C3-C8 cycloalkyl, C ^ -C7 cycloalkenyl, and ri, with the proviso that both R3 and R are not hydrogen; wherein such R and R4 are independently unsubstituted or substituted with one or more substituents independently selected from the group consisting of carboxy, C3-C8 cycloalkyl, C5-C7 cycloalkenyl, halo, hydroxy, nitro, trifluoromethyl, C? Straight chain or branched chain, straight or branched chain C2-C6 alkenyl, Ci-Cβ alkoxy, C2-C2 alkenyloxy, phenoxy, benzyloxy, amino, and Ar2; Rr, and R6 are independently selected from the group consisting of hydrogen, straight or branched chain Ci-Ce alkyl, straight or branched chain C2-Cd alkenyl, C3-C8 cycloalkyl, C5-C7 cycloalkenyl, Arl and halo; Ari and Ar2 are independently 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 such Ari and Ar2 are independently unsubstituted or substituted with one or more substituents independently selected from the group consisting of halo, hydroxy, nitro, trifluoromethyl, alkyl of straight or branched chain Ci-Cß, straight or branched chain C2-C6 alkenyl, Ci-Cβ alkoxy, C2-C6 alkenyloxy, phenoxy, benzyloxy, and amino. 26. The method according to claim 25, characterized in that: R4 is hydrogen; and R3 is substituted with one or more substituents independently selected from the group consisting of carboxy, Ci-Ce alkoxy, C? -Cf alkenyloxy, phenoxy, and benzyloxy. 27. The method according to claim 25, characterized in that the prodrug is selected from the group consisting of: 2- [(benzylmethoxyphosphinyl) methyl] pentanedioic acid; 2- [(benzyloxyethoxyphosphyl) methyl] pentanedioic acid; 2- [(benzylpropoxyphosphinyl) methyl] pentanedioic acid; 2- [(benzylacetoxyphosphyl) methyl] pentanedioic acid; 2- [(benzylbenzyloxyphosphinyl) methyl] pentanedioic acid; 2- [(Benzyl (1-oxopropoxy) methoxyphosphinyl) methyl] pentanedioic acid; 2- [(pentafluorobenzylmethoxyphosphinyl) methyl pentanedioic acid; 2- [(pentafluorobenzyl-ethoxy-phosphinyl) -methyl] -pentanedioic acid; 2- [(pentafluorobenzylopropoxyphosphinyl) methyl] pentanedioic acid; 2- [(pentafluorobenzylcoxethoxyphosphinyl) methyl] pentanedioic acid; 2- [(pentafluorobenzyl (1-oxo-propoxy) phosphinyl) methyl] pentandioic; and the pharmaceutically acceptable salts and hydrates thereof. 28. A method for effecting an abnormality of glutamate in an animal, characterized in that it comprises administering an effective amount of a prodrug of a NAALADase inhibitor to such an animal. 29. The method according to claim 28, characterized in that the prodrug is administered in combination with at least one additional therapeutic agent. 30. The method of compliance with the claim 28, characterized in that the neuronal activity is selected from the group consisting of stimulation of damaged neurons, promotion of neuronal regeneration, prevention of neurodegeneration, and treatment of a neurological disorder. 31. The method of compliance with the claim 30, characterized in that the neurological disorder is 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, demyelination disease and neurological disorder related to neurodegeneration. 32. The method of compliance with the claim 31, characterized in that peripheral neuropathy is caused by the Guillain-Barré syndrome. 33. The method according to claim 31, characterized in that the demyelinating disease is multiple sclerosis. 34. The method according to claim 31, characterized in that the neurological disorder is related to the neurodegeneration that is selected from the group consisting of Alzheimer's Disease, Parkinson's Disease, and Amyotrophic Lateral Sclerosis. 35. The method according to claim 28, characterized in that the NAALADase inhibitor is a hydroxyphosphinyl derivative of glutamate derived from the formula I: or a pharmaceutically acceptable salt or hydrate thereof, wherein: X is CR3R4, O or NR5; Ri and R5 are independently selected from the group consisting of hydrogen, straight or branched chain C?-Cg alkyl, straight or branched chain C2-Cg alkenyl, C3-C8 cycloalkyl, C5-C7 cycloalkenyl and Ar , wherein such Ri and Ry, are independently unsubstituted or substituted with one or more substituents independently selected from the group consisting of carboxy, C3-C8 cycloalkyl, C5-C7 cycloalkenyl, halo, hydroxy, nitro, trifluoromethyl, Ci-Cβ straight or branched chain, C2-Ce alkenyl of straight or branched chain, Ci-Cg alkoxy, alkenyloxy of β-Cg, phenoxy, benzyloxy, amino, and Ar; R3 and R4 are independently selected from the group consisting of hydrogen, straight or branched chain Ci-Ce alkyl, straight or branched chain C2-Ce alkenyl, C3-Cs cycloalkyl, C5-C7 cycloalkenyl, Ar, and halo; R 2 are selected from the group consisting of hydrogen, C 1 -Cg straight or branched chain alkyl, C 2 -Cg straight or branched chain alkenylene, C 3 -C 8 cycloalkyl, C 5 -C 7 cycloalkenyl and Ar, wherein R2 is substituted or unsubstituted with one or more substituents independently selected from the group consisting of carboxy, C3-C8 cycloalkyl, C5-C7 cycloalkenyl, halo, hydroxy, nitro, trifluoromethyl, straight or branched chain Ci-Cs alkyl , straight or branched chain C2-Cd alkenyl, Ci-Cg alkoxy, C2-C6 alkenyloxy, phenoxy, benzyloxy, amino, and Ar; 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, in which such Ai is substituted or unsubstituted with one or more substituents independently selected from the group consisting of carboxy, halo, hydroxy, nitro, trifluoromethyl, C? C6 straight or branched chain, straight or branched chain C2-Cß alkylene, Ci-Cß alkoxy, C2-C6 alkenyloxy, phenoxy, benzyloxy, and amino. 36. The method of compliance with the claim 35, characterized in that X is CH2. 37. The method according to the claim 36, characterized in that R2 is substituted with carboxy. 38. The method of compliance with the claim 37, characterized in that: R1 is hydrogen, straight or branched chain C? ~C4 alkyl, straight or branched chain C2-C4 alkenyl, C3-Cs cycloalkyl, C ^-C ciclocycloalkenyl; , benzyl or phenyl, wherein Ri is substituted or unsubstituted with one or more substituents independently selected from the group consisting of carboxy, C3-C8 cycloalkyl, C5-C7 cycloalkenyl, halo, hydroxy, nitro, trifluoromethyl, C-alkyl ? C6 straight or branched chain, straight or branched chain C2-C6 alkenyl, C? -C alkoxy, C? -C4 alkenyloxy, phenoxy, benzyloxy, amino, benzyl, and phenyl; and R2 is C? -C2 alkyl. 39. The method according to claim 38, characterized in that the derivatized hydroxyphosphinyl derivative of glutamate is selected from the group consisting of: 2- (phosphonomethyl) pentanedioic acid; 2- (phosphonomethyl) succinic acid; 2- [[(2-carboxyethyl) hydroxyphosphinyl] methyl] pentanedioic acid; 2- [(benzylhydroxyphosphinyl) methylpentane-dioic acid; 2- [(phenylhydroxyphosphinyl) methyl] pentanedioic acid; 2- [[((Hydroxy) phenylmethyl) hydroxyphosphinyl] -methyl] pentanedioic acid; 2- [(butylhydroxyphosphinyl) methyl] pentanedioic acid; 2- [[(3-methylbenzyl) hydroxyphosphinyl] methyl] -pentanedioic acid; 2- [(3-phenylpropylhydroxy phosphinyl) methyl] -pentanedioic acid; 2- [[(4-fluorophenyl) hydroxyphosphinylmethyl] -pentanedioic acid; 2- [(Methylhydroxyphosphinyl) methyl] pentanedioic acid; 2- (phenylethylhydroxyphosphinyl) methyl] -pentanedioic acid; 2- [[(4-methylbenzyl) hydroxyphosphinyl] methyl] -pentanedioic acid; 2- [[(4-fluorobenzyl) hydroxyphosphinyl] methyl] -pentanedioic acid; 2- [[(4-methoxybenzyl) hydroxyphosphinyl] methyl] -pentanedioic acid; 2- [[3-trifluoromethyl Ibenzyl] hydroxyphosphinyl] -methyl] pentanedioic acid; 2- [[(2-fluorobenzyl) hydroxyphosphinyl] methyl] -pentanedioic acid; 2- [[(pentafluorobenzyl) hydroxyphosphinyl] -methyl] pentanedioic acid; 2- [(Phenylpro-2-enyl) hydroxyphosphinyl] ethyl] -pentanedioic acid; 2- [(aminomethyl) hydroxyphosphinyl] methyl] -pentanedioic acid; 2- [(aminoethyl) hydroxyphosphinyl] methyl] -pentanedioic acid 2- [[(aminopropyl) hydroxyphosphinyl] methyl] -pentanedioic acid; and pharmaceutically acceptable salts and hydrates thereof. 40. The method according to claim 39, characterized in that the derivatized hydroxyphosphinyl derivative of glutamate is 2- (phosphonomethyl) pentanedioic acid or a pharmaceutically acceptable salt or hydrate thereof. 41. The method according to claim 28, characterized in that the prodrug is a compound of the formula II or a pharmaceutically acceptable salt or hydrate thereof, wherein: X is CR5Re, NR7 or O; Ri and R7 are independently selected from the group consisting of hydrogen, C1-C9 alkyl straight or branched chain, straight or branched chain C2-Cg alkenyl, C3-C8 cycloalkyl, C5-C7 cycloalkenyl and Arx, wherein such Ri and R7 are independently unsubstituted or substituted with one or more substituents independently selected from the group consisting of carboxy, C3-Cs cycloalkyl, C5-C7 cycloalkenyl, halo, hydroxy, nitro, trifluoromethyl, Ci-C alkyl ? straight or branched chain, straight or branched chain C2-C2 alkenyl, Ci-Cg alkoxy, C2-Cg alkenyloxy, phenoxy, benzyloxy, amino, and Ar2; R2 is selected from the group consisting of hydrogen, straight or branched chain Ci-Cg alkyl, straight or branched chain C2-C9 alkenyl, C3-C8 cycloalkyl, C5-C7 cycloalkenyl and Ari, wherein such R , is substituted or unsubstituted with one or more substituents independently selected from the group consisting of carboxy, C3-C8 cycloalkyl, C5-C7 cycloalkenyl, halo, hydroxy, nitro, trifluoromethyl, straight or branched chain Ci-Cs alkyl , straight or branched chain C2-Ce alkenyl, Ci-Ce alkoxy, C6-C6 alkenyloxy, phenoxy, benzyloxy, amino, and Ar2; R3 and R4 are independently selected from the group consisting of hydrogen, carboxy, straight or branched chain C1-C9 alkyl, straight or branched chain C2-Cg alkenyl, C3-C8 cycloalkyl, Ct cycloalkenyl, -C7, and Ari, with the proviso that both R and R4 are not hydrogen; wherein such R3 and R4 are independently unsubstituted or substituted with one or more substituents independently selected from the group consisting of carboxy, C3-Cs cycloalkyl, C5-C7 cycloalkenyl, • halo, hydroxy, nitro, trifluoromethyl, Ci-C, straight or branched chain, straight or branched chain C2-Cd alkenyl, Ci-Cβ alkoxy, C? -C6 alkenyloxy, phenoxy, benzyloxy, amino, and Ar ?; R5 and Re are independently selected from the group consisting of hydrogen, straight or branched chain Ci-Ce alkyl, straight or branched chain C2-C6 alkenyl, C3-C8 cycloalkyl, C5-C7 cycloalkenyl, Arx, and halo; Arx and Ar2 are independently 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 such Ari and Ar2 are independently unsubstituted or substituted with one or more substituents independently selected from the group consisting of halo, hydroxy, nitro, trifluoromethyl, alkyl of straight or branched chain Ci-Cß, straight or branched chain C-C6 alkenyl, Ci-Ce alkoxy, C2-Cd alkenyloxy, phenoxy, benzylaxy, and amino. 42. The method according to claim 41, characterized in that: R4 is hydrogen; and R3 is substituted with one or more substituents independently selected from the group consisting of carboxy, Ci-Cß alkoxy, C2-Cc alkenyloxy, phenoxy, and benzyloxy. 43. The method according to claim 42, characterized in that the prodrug is selected from the group consisting of: 2- [(benzylmethoxyphosphinyl) methyl] pentanedioic acid; 2- [(benzyloxyethoxyphosphyl) methyl] pentanedioic acid; 2 - [(benzylpropoxyphosphinyl) methyl] pentanedioic acid; 2- [(benzylacetoxyphosphyl) methyl] pentanedioic acid; 2- [(benzylbenzyloxyphosphinyl) methyl] pentanedioic acid; 2- [(Benzyl (1-oxopropoxy) methoxyphosphinyl) methyl] pentanedioic acid; 2- [(pentafluorobenzylmethoxyphosphinyl) methyl pentanedioic acid; - acid. 2- [(pentafluorobenzyl) ethoxyphosphinyl) methyl] pentanedioic; 2- [(pentafluofobeñcilopropoxifosfinil) methyl] pentanedioic acid; 2- [(pentafluorobenzylcoxethoxyphosphinyl) ethyl] pentanedioic acid; 2- [(pentafluorobenzyl (1-oxo-propoxy) phosphinyl) methyl] pentandioic; and the pharmaceutically acceptable salts and hydrates thereof. 44. A method for treating a compulsive disorder, characterized in that it comprises administering an effective amount of a prodrug of a NAALADase inhibitor to a patient in need thereof. 45. The method according to the claim 44, characterized in that the prodrug is administered in combination with at least one additional therapeutic agent. 46. The method according to claim 44, characterized in that the compulsive disorder is selected from the group consisting of drug dependence, eating disorders, pathological gambling, attention deficit disorder (ADD) and Tourette's syndrome. 47. The method according to claim 46, characterized in that the drug dependence is alcohol dependence. 48. The method according to claim 46, characterized in that the drug dependence is nicotine dependence. 49. The method according to claim 44, characterized in that the NAALADase inhibitor is a hydroxyphosphinyl derivative of glutamate derived from the formula I: or a pharmaceutically acceptable salt or hydrate thereof, wherein: X is CR3R4, O or NR5; Ri and R5 are independently selected from the group consisting of hydrogen, straight or branched chain Ci-Cg alkyl, straight or branched chain C2-Cg alkenyl, C3-C8 cycloalkyl, C5-C7 cycloalkenyl and Ar, where such Ri and Rr, are independently unsubstituted or substituted with one or more substituents independently selected from the group consisting of carboxy, C3-C8 cycloalkyl, C5-C7 cycloalkenyl, halo, hydroxy, nitro, trifluoromethyl, Ci-alkyl Straight chain or branched chain C, straight or branched chain C2-C6 alkenyl, C1-C9 alkoxy, C-Cg alkenyloxy, phenoxy, benzyloxy, amino, and Ar; R and R4 are independently selected from the group consisting of hydrogen, straight or branched chain Ci-Ce alkyl, straight or branched chain C2-C6 alkenyl, C3-C8 cycloalkyl, C5-C7 cycloalkenyl, Ar, and halo; R2 are selected from the group consisting of hydrogen, straight or branched chain C1-C9 alkyl, straight or branched chain C2-Cg alkenylene, C3-C8 cycloalkyl, C5-C7 cycloalkenyl and Ar, wherein such R2 is substituted or unsubstituted with one or more substituents independently selected from the group consisting of carboxy, C3-C8 cycloalkyl, C5-C7 cycloalkenyl, halo, hydroxy, nitro, trifluoromethyl, straight or branched chain Ci-Ce alkyl, linear or branched chain C- Ce alkenyl, C?-C6 alkoxy, C 2 -C 6 alkenyloxy, phenoxy, benzyloxy, amino, and Ar; 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 substituted or unsubstituted with one or more substituents independently selected from the group consisting of carboxy, halo, hydroxy, nitro, trifluoromethyl, C? C6 straight or branched chain, straight or branched chain C2-C6 alkylene, Ci-Ce alkoxy, C2-Cg alkenyloxy, phenoxy, benzyloxy, and amino. 50. The method according to claim 49, characterized in that X is CH2. 51. The method of compliance with the claim 50, characterized in that R2 is substituted with carboxy. 52. The method according to claim 51, characterized in that: R1 is hydrogen, straight or branched chain C? -C4 alkyl, straight or branched chain C2-C alkenyl, C3-C8 cycloalkyl, C5 cycloalkenyl -C7, benzyl or phenyl, wherein Ri is substituted or unsubstituted with one or more substituents independently selected from the group consisting of carboxy, C3-C8 cycloalkyl, C5-C7 cycloalkenyl, halo, hydroxy, nitro, trifluoromethyl, alkyl of straight or branched chain C'-Ce, straight or branched chain C2-C6 alkenyl, C?-C4 alkoxy, C?-C4 alkenyloxy, phenoxy, benzyloxy, amino, benzyl, and phenyl; and R2 is C? -C alkyl. 53. The method according to claim 52, characterized in that the derivatized hydroxyphosphinyl derivative of glutamate is selected from the group consisting of: 2- (phosphonomethyl) pentanedioic acid; 2- (phosphonomethyl) succinic acid; 2- [[(2-carboxyethyl) hydroxyphosphinyl] methyl] pentanedioic acid; 2- [(benzylhydroxyphosphinyl) methylpentanedioic acid; 2- [(phenylhydroxyphosphinyl) methyl] pentanedioic acid; 2- [[((Hydroxy) phenylmethyl) hydroxyphosphinyl] methyl] pentanedioic acid; 2- [(butylhydroxyphosphinyl) methyl] pentanedioic acid; 2- [tomethylbenzyl) hydroxyphosphinyl] methyl] pentanedioic acid; 2- [(3-phenylpropylhydroxyphosphinyl) methyl] pentanedioic acid; 2 - [[(4-fluorophenyl) hydroxyphosphinylmethyl] pentanedioic acid; 2- [(Methylhydroxyphosphinyl) methyl] pentanedioic acid; 2- (phenylethylhydroxyphosphinyl) methyl] pentanedioic acid; 2 - [[(4-methylbenzyl) hydroxyphosphinyl] methyl] pentanedioic acid; 2- [[(4-Fluorobenzyl) hydroxyphosphinyl] methy1-pentanedioic acid; 2 - [[(4-methoxybenzyl) hydroxyphosphinyl] methyl] pentanedioic acid; 2- [[3-trifluoromethylbenzyl] hydroxyphosphinyl] methyl] pentanedioic acid; 2- [[(2-Fluorobenzyl) hydroxyphosphinyl] methyl] pentanedioic acid 2- [[(pentafluorobenzyl) hydroxyphosphinyl] methyl] pentanedioic acid; 2- [(Phenylpro-2-enyl) hydroxyphosphinyl] methyl] pentanedioic acid; 2 - [(aminomethyl) hydroxyphosphinyl] methyl] pentanedioic acid; 2- [(Aminoethyl) hydroxyphosphinyl] methyl] pentanedioic acid 2- [[(aminopropyl) hydroxyphosphinyl] methyl] pentanedioic acid; and pharmaceutically acceptable salts and hydrates thereof. 54. The method of compliance with the claim 53, characterized in that the derivatized hydroxyphosphinyl derivative of glutamate is 2- (phosphonomethyl) pentanedioic acid or a pharmaceutically acceptable salt or hydrate thereof. 55. The method according to claim 44, characterized in that the prodrug is a compound of the formula II or a pharmaceutically acceptable salt or hydrate thereof, wherein: X is CR5R6, NR7 or O; Ri and R7 are independently selected from the group consisting of hydrogen, straight or branched chain C1-C9 alkyl, straight or branched chain C2-Cg alkenyl, C3-C8 cycloalkyl, C5-C7 cycloalkenyl and Arx, wherein such Ri and R7 are independently unsubstituted or substituted with one or more substituents independently selected from the group consisting of carboxy, C3-C8 cycloalkyl, Cs-C7 cycloalkenyl, halo, hydroxy, nitro, trifluoromethyl, Ci-Cc alkyl straight or branched chain, straight or branched chain C2-C6 alkenyl, Ci-Cg alkoxy, Cj-Cg alkenyloxy, phenoxy, benzyloxy, amino, and Ar ?; R 2 is selected from the group consisting of hydrogen, straight or branched chain C 1 -Cg alkyl, straight or branched chain C 1 -Cg alkenyl, C 3 -C 8 cycloalkyl, C 5 -C 7 cycloalkenyl and Ari, wherein such R2 is substituted or unsubstituted with one or more substituents independently selected from the group consisting of carboxy, C3-C8 cycloalkyl, C5-C7 cycloalkenyl, halo, hydroxy, nitro, trifluoromethyl, straight chain Ci-C3 alkyl or branched, straight or branched chain C 1 -Ce alkenyl, Ci-Cβ alkoxy, C 2 -C 6 alkenyloxy, phenoxy, benzyloxy, amino, and Ar 2; R3 and R4 are independently selected from the group consisting of hydrogen, carboxy, straight or branched chain C1-C9 alkyl, straight or branched chain C2-C9 alkenyl, C3-C8 cycloalkyl, C-C7 cycloalkenyl, and Ari, with the proviso that both R3 and R4 are not hydrogen; wherein such R and R4 are independently unsubstituted or substituted with one or more substituents independently selected from the group consisting of carboxy, C3-C8 cycloalkyl, C5-C7 cycloalkenyl, halo, hydroxy, nitro, trifluoromethyl, C? -Cu straight or branched chain, straight or branched chain C2-C6 alkenyl, Ci-Ce alkoxy, C2-C2 alkenyloxy, phenoxy, benzyloxy, amino, and Ar2; R5 and Re are independently selected from the group consisting of hydrogen, straight or branched chain Ci-Cß alkyl, straight or branched chain C2-Cg alkenyl, C3-C8 cycloalkyl, C5-C7 cycloalkenyl, Ari, and halo; Ari and Ar2 are independently 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 such ri and Ar2 are independently unsubstituted or substituted with one or more substituents independently selected from the group consisting of halo, hydroxy, nitro, trifluoromethyl, straight or branched chain Ci-Cs alkyl, C2- alkenyl Linear or branched chain ce, Ci-Cβ alkoxy, C2-C6 alkenyloxy, phenoxy, benzyloxy, and amino. 56. The method according to claim 55, characterized in that: R4 is hydrogen; and R3 is substituted with one or more substituents independently selected from the group consisting of carboxy, Ci-Cß alkoxy, C2-C, alkynyloxy, phenoxy, and benzyloxy. 57. The method according to claim 56, characterized in that it is selected from the group consisting of: 2- [(benzylmethoxyphosphinyl) methyl] pentanedioic acid; 2- [(benzyloxyethoxyphosphyl) methyl] pentanedioic acid; 2- [(benzylpropoxyphosphinyl) methyl] pentanedioic acid; 2- [(benzylacetoxyphosphyl) methyl] pentanedioic acid; 2- [(benzylbenzyloxyphosphinyl) methyl] pentanedioic acid; 2- [(Benzyl (1-oxopropoxy) methoxy phosphinyl) methyl] pentanedioic acid 2- [(pentafluorobenzylmethoxyphosphinyl) methyl pentanedioic acid; 2- [(pentafluorobenzyl-ethoxy-phosphinyl) -methyl] -pentanedioic acid; 2- [(pentafluorobenzylopropoxyphosphinyl) methyl] pentanedioic acid; 2- [(pentafluorobenzyl-acetoxyphosphinyl) methyl] pentanedioic acid; 2- [(pentafluorobenzyl (1-oxo-propoxy) phosphinyl) methyl] pentandioic; and the pharmaceutically acceptable salts and hydrates thereof. - 58. A method for treating a disease of the prostate in an animal, characterized in that it comprises administering an effective amount of a prodrug of a NAALADase inhibitor to said animal. 59. The method according to claim 58, characterized in that the prodrug is administered in combination with at least one additional therapeutic agent. 60. The method according to claim 58, characterized in that the disease of the prostate is prostate cancer or benign prostatic hyperplasia. 61. The method according to claim 58, characterized in that the NAALADase inhibitor is a hydroxyphosphinyl derivative of glutamate derived from the Formula I: or a pharmaceutically acceptable salt or hydrate thereof, wherein: X is CR3R, 0 or NR5; Ri and R5 are independently selected from the group consisting of hydrogen, straight or branched chain C1-C9 alkyl, straight or branched chain C2-Cg alkenyl, C3-C8 cycloalkyl, C5-C7 cycloalkenyl and Ar, wherein such Ri and Rs are independently unsubstituted or substituted with one or more substituents independently selected from the group consisting of carboxy, C3-Cs cycloalkyl, C5-C7 cycloalkenyl, halo, hydroxy, nitro, trifluoromethyl, C? Linear or branched chain Cs, straight or branched chain C2-C6 alkenyl, Ci-Cg alkoxy, C2-Cg alkenyloxy, phenoxy, benzyloxy, amino, and Ar; R3 and R4 are independently selected from the group consisting of hydrogen, straight or branched chain Ci-Cß alkyl, straight or branched chain C2-C6 alkenyl, C3-C8 cycloalkyl, C5-C7 cycloalkenyl, Ar, and halo; R2 are selected from the group consisting of hydrogen, straight or branched chain C1-C9 alkyl, straight or branched chain C2-Cg alkenylene, C3-C8 cycloalkyl, C5-C7 cycloalkenyl and Ar, wherein such R2 is substituted or unsubstituted with one or more substituents independently selected from the group consisting of carboxy, C3-C8 cycloalkyl, C5-C7 cycloalkenyl, halo, hydroxy, nitro, trifluoromethyl, straight or branched chain Ci-Cs alkyl, straight-chain or branched C -C6 alkenyl, Ci-Cß alkoxy, C?-C6 alkenyloxy, phenoxy, benzyloxy, amino, and Ar; 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 substituted or unsubstituted with one or more substituents independently selected from the group consisting of carboxy, halo, hydroxy, nitro, trifluoromethyl, C? C6 straight or branched chain, straight or branched chain C2-C6 alkylene, Ci-Cß alkoxy, Cj-C6 alkenyloxy, phenoxy, benzyloxy, and amino. 62. The method according to claim 61, characterized in that X is CH2. 63. The method according to claim 62, characterized in that R2 is substituted with carboxy. 64. The method of compliance with the claim 63, characterized in that: R 1 is hydrogen, C 1 -C 4 straight or branched chain alkyl, straight or branched chain C 2 -C 4 alkenyl, C 3 -C 8 cycloalkyl, C 5 -C 7 cycloalkenyl, benzyl or phenyl, wherein Ri is substituted or unsubstituted with one or more substituents independently selected from the group consisting of carboxy, C3-C8 cycloalkyl, C5-C7 cycloalkenyl, halo, hydroxy, nitro, trifluoromethyl, straight or branched chain Ci-Cs alkyl , straight or branched chain C2-C6 alkenyl, C1-C4 alkoxy, C2-C4 alkenyloxy, phenoxy, benzyloxy, amino, benzyl, and phenyl; and R? it is C? ~ C2 alkyl. 65. The method of compliance with the claim 64, characterized in that the derivatized glutamate hydroxyphosphinyl derivative is selected from the group consisting of: 2- (phosphonomethyl) pentanedioic acid; 2- (phosphonomethyl) succinic acid; 2- [[(2-carboxyethyl) hydroxyphosphinyl] methyl] pentanedioic acid; 2- [(benzylhydroxyphosphinyl) methylpentanedioic acid; 2- [(phenylhydroxyphosphinyl) methyl] pentanedioic acid; 2- [[((Hydroxy) phenylmethyl) hydroxyphosphinyl] methyl] pentanedioic acid; 2- [(butylhydroxyphosphinyl) methyl] pentanedioic acid; 2- [EO-methylbenzyl) hydroxyphosphinyl] methyl] pentanedioic acid; 2 - [(3-phenylpropylhydroxyphosphinyl) methyl] pentanedioic acid; 2 - [[(4-fluorophenyl) hydroxyphosphinylmethyl] pentanedioic acid; 2- [(Methylhydroxyphosphinyl) methyl] pentanedioic acid; 2- (phenylethylhydroxyphosphinyl) methyl] pentanedioic acid; 2 - [[(4-methylbenzyl) hydroxyphosphinyl] methyl] pentanedioic acid; acid - 2 - [[(4-fluorobenzyl) hydroxyphosphinyl] methylpentanedioic acid; 2 - [[(4-methoxybenzyl) hydroxyphosphinyl] methyl] pentanedioic acid; 2- [[3-trifluoromethylbenzyl] hydroxyphosphinyl] methyl] pentanedioic acid; 2 - [[(2-fluorobenzyl) hydroxyphosphinyl] methyl] pentanedioic acid; 2- [[(pentafluorobenzyl) hydroxyphosphinyl] methyl] pentanedioic acid; acid 2- [(Phenylpro-2-enyl) hydroxyphosphinyl] methyl] pentanedioic; 2- [(aminomethyl) hydroxyphosphinyl] methyl] pentanedioic acid; 2- [(Aminoethyl) hydroxyphosphinyl] methyl] pentanedioic acid 2- [[(aminopropyl) hydroxyphosphinyl] methyl] pentanedioic acid; and pharmaceutically acceptable salts and hydrates thereof. 66. The method according to claim 65, characterized in that the derivatized hydroxyphosphinyl derivative of glutamate is 2- (phosphonomethyl) pentanedioic acid or a pharmaceutically acceptable salt or hydrate thereof. 67. The method according to claim 58, characterized in that the prodrug is a compound of the formula II or a pharmaceutically acceptable salt or hydrate thereof, wherein: X is CR5R6, NR7 or O; Ri and R7 are independently selected from the group consisting of hydrogen, straight or branched chain C1-C9 alkyl, straight or branched chain C2-Cg alkenyl, C3-C8 cycloalkyl, C5-C7 cycloalkenyl and Ari, where such Ri and R? are independently unsubstituted or substituted with one or more substituents independently selected from the group consisting of carboxy, C3-C8 cycloalkyl, C5-C7 cycloalkenyl, halo, hydroxy, nitro, trifluoromethyl, C? -Ct alkyl) straight chain or branched, straight or branched chain C2-C6 alkenyl, C1-C9 alkoxy, C2-Cg alkenyloxy, phenoxy, benzyloxy, amino, and Ar ?; R2 is selected from the group consisting of hydrogen, straight or branched chain C1-C9 alkyl, straight-chain or branched C-Cg alkenyl, C3-C8 cycloalkyl, C5-C7 cycloalkenyl, and Ari, wherein such R ? is substituted or unsubstituted with one or more substituents independently selected from the group consisting of carboxy, C3-C8 cycloalkyl, C5-C7 cycloalkenyl, halo, hydroxy, nitro, trifluoromethyl, straight or branched chain Ci-Ce alkyl, straight or branched chain C2-C6 alkenyl, Ci-Cß alkoxy, C-C6 alkenyloxy, phenoxy, benzyloxy, amino, and Ar2; R3 and R4 are independently selected from the group consisting of hydrogen, carboxy, straight or branched chain C1-C9 alkyl, straight or branched chain C2-C9 alkenyl, C3-C8 cycloalkyl, Cr cycloalkenyl, -C7, and Ari, with the proviso that both R3 and R4 are not hydrogen; wherein such R3 and R4 are independently unsubstituted or substituted with one or more substituents independently selected from the group consisting of carboxy, C3-C8 cycloalkyl, C5-C7 cycloalkenyl, halo, hydroxy, nitro, trifluoromethyl, Ci-alkyl Linear or branched chain co, straight or branched chain C2-C6 alkenyl, C-C alkoxy, C? -C6 alkenyloxy, phenoxy, benzyloxy, amino, and? R ?; R5 and R6 are independently selected from the group consisting of hydrogen, straight or branched chain Ci-Cß alkyl, straight or branched chain C2-C6 alkenyl, C3-C8 cycloalkyl, C5-C7 cycloalkenyl, Ari, and halo; Art and Ar2 are independently 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 such Ari and Ar2 are independently unsubstituted or substituted with one or more substituents independently selected from the group consisting of halo, hydroxy, nitro, trifluoromethyl, alkyl of straight or branched chain Ci-Cß, straight or branched chain C2-C6 alkenyl, Ci-Cβ alkoxy, C2-C6 alkenyloxy, phenoxy, benzyloxy, and amino. 68. The method according to claim 67, characterized in that: R4 is hydrogen; and R 3 is substituted with one or more substituents independently selected from the group consisting of carboxy, Ci-Cβ alkenyloxy of C?-C6, phenoxy, and benzyloxy. 69. The method according to claim 68, characterized in that it is selected from the group consisting of: 2- [(benzylmethoxyphosphinyl) methyl] pentanedioic acid 2- [(benzyloxyethoxyphosphinyl) methyl] pentanedioic acid; 2- [(benzylpropoxyphosphinyl) methyl] pentanedioic acid; 2- [(benzylacetoxyphosphyl) methyl] pentanedioic acid; 2- [(benzylbenzyloxyphosphinyl) methyl] pentanedioic acid; 2- [(Benzyl (1-oxopropoxy) methoxyphosphinyl) methyl] pentanedioic acid; 2- [(pentafluorobenzylmethoxyphosphinyl) methyl pentanedioic acid; 2- [(pentafluorobenzyl-ethoxy-phosphinyl) -methyl] -pentanedioic acid; 2- [(pentafluorobenzylopropoxyphosphinyl) methyl] pentanedioic acid; 2- [(pentafluorobenzylcoxethoxyphosphinyl) methyl] pentanedioic acid; 2- [(pentafluorobenzyl (1-oxo-propoxy) phosphinyl) methyl] pentandioic; and the pharmaceutically acceptable salts and hydrates thereof. 70. A pharmaceutical composition characterized in that it comprises: (i) an effective amount of a prodrug of a NAALADase inhibitor; and (ii) a pharmaceutically acceptable carrier. 71. The pharmaceutical composition according to claim 70, characterized in that the NAALADase inhibitor is a hydroxyphosphinyl derivative of glutamate derived from the formula I: or a pharmaceutically acceptable salt or hydrate thereof, wherein: X is CR3R4, 0 or NR5; Ri and R5 are independently selected from the group consisting of hydrogen, straight or branched chain Ci-Cg alkyl, straight or branched chain C2-Cg alkenyl, C3-C8 cycloalkyl, C5-C7 cycloalkenyl and Ar, where such Ri and R > , are independently unsubstituted or substituted with one or more substituents independently selected from the group consisting of carboxy, C3-C8 cycloalkyl, C5-C7 cycloalkenyl, halo, hydroxy, nitro, trifluoromethyl, Ci-C alkyl, -, straight or branched chain, straight or branched chain C2-C6 alkenyl, Ci-Cg alkoxy, C: -Cg alkenyloxy, phenoxy, benzyloxy, amino, and Ar; R3 and R4 are independently selected from the group consisting of hydrogen, straight or branched chain Ci-Cß alkyl, straight or branched chain C2-C6 alkenyl, C3-C8 cycloalkyl, C5-C7 cycloalkenyl, Ar, and halo; R2 are selected from the group consisting of hydrogen, straight or branched chain C1-C9 alkyl, straight or branched chain C2-Cg alkenylene, C3-C8 cycloalkyl, C5-C7 cycloalkenyl and Ar, wherein such R2 is substituted or unsubstituted with one or more substituents independently selected from the group consisting of carboxy, C3-C8 cycloalkyl, C5-C7 cycloalkenyl, halo, hydroxy, nitro, trifluoromethyl, straight or branched chain CI-CT alkyl, linear or branched chain C2-Ce alkenyl, Ci-Ce alkoxy, C2-C6 alkenyloxy, phenoxy, benzyloxy, amino, and Ar; 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 substituted or unsubstituted with one or more substituents independently selected from the group consisting of carboxy, halo, hydroxy, nitro, trifluoromethyl, straight or branched chain Ci-Cß alkyl, C2 alkylene -C6 straight or branched chain, C? -C? Alkoxy, C -C6 alkenyloxy, phenoxy, benzyloxy, and amino. 72. The pharmaceutical composition according to claim 71, characterized in that X is CH2. 73. The pharmaceutical composition according to claim 72, characterized in that R2 is substituted with carboxy. 74. The pharmaceutical composition according to claim 73, characterized in that: R1 is hydrogen, straight or branched chain C? -C4 alkyl, straight or branched chain C2-C4 alkenyl, C3-C8 cycloalkyl, cycloalkenyl C ^, - C7, benzyl or phenyl, wherein Ri is substituted or unsubstituted with one or more substituents independently selected from the group consisting of carboxy, C3-C8 cycloalkyl, Cs-C7 cycloalkenyl, halo, hydroxy, nitro, trifluoromethyl, straight or branched chain C -C alkyl, straight or branched chain C2-Ce alkenyl, C1-C4 alkoxy, C2-C4 alkenyloxy, phenoxy, benzyloxy, amino, benzyl, and phenyl; and R2 is C? -C2 alkyl. 75. The pharmaceutical composition according to claim 74, characterized in that the hydroxyphosphinyl derivative of the derivatized glutamate is selected from the group consisting of 2- (phosphonomethyl) pentanedioic acid; 2- (phosphonomethyl) succinic acid; 2- [[(2-carboxyethyl) hydroxyphosphinyl] methyl] pentanedioic acid; 2- [(benzylhydroxyphosphinyl) methylpentanedioic acid; 2- [(phenylhydroxyphosphinyl) methyl] pentanedioic acid; 2- [[((Hydroxy) phenylmethyl) hydroxyphosphinyl] methyl] pentanedioic acid; 2- [(butylhydroxyphosphinyl) methyl] pentanedioic acid; 2- [[(3-methylbenzyl) hydroxyphosphinyl] methyl] pentanedioic acid; 2- [(3-phenylpropylhydroxyphosphinyl) methyl] pentanedioic acid; 2 - [[(4-fluorophenyl) hydroxyphosphinylmethyl] pentanedioic acid; 2- [(Methylhydroxyphosphinyl) methyl] pentanedioic acid; 2- (phenylethylhydroxyphosphinyl) methyl] pentanedioic acid; 2 - [[(4-methylbenzyl) hydroxyphosphinyl] methyl] pentanedioic acid; 2 - [[(4-fluorobenzyl) hydroxyphosphinyl] methylpentanedioic acid; 2 - [[(4-methoxybenzyl) hydroxyphosphinyl] methyl] pentanedioic acid; 2- [[3-trifluoromethylbenzyl] hydroxyphosphinyl] methyl] pentanedioic acid; 2- [[(2-fluorobenzyl) hydroxyphosphinyl] methyl] pentanedioic acid; acid 2- [[(pentafluorobenzyl) hydroxyphosphinyl] methyl] pentanedioic; 2- [(Phenylpro-2-enyl) hydroxyphosphinyl] methyl] pentanedioic acid; 2- [(aminomethyl) hydroxyphosphinyl] methyl] pentanedioic acid; 2- [(aminoethyl) hydroxyphosphinyl] methyl-pentanedioic acid 2- [[(aminopropyl) hydroxyphosphinyl] methyl] pentanedioic acid; and pharmaceutically acceptable salts and hydrates thereof. 76. The pharmaceutical composition according to claim 75, characterized in that the hydroxyphosphinyl derivative of glutamate derivative is 2-phosphonomethyl) pentanedioic acid or a pharmaceutically acceptable salt or hydrate thereof. 77. The pharmaceutical composition according to claim 70, characterized in that the prodrug is a compound of the formula II or a pharmaceutically acceptable salt or hydrate thereof, wherein: X is CR5R6, NR7 or O; Ri and R7 are independently selected from the group consisting of hydrogen, straight or branched chain Cj.-Cg alkyl, straight or branched chain C2-Cg alkenyl, C3-C8 cycloalkyl, C5-C7 cycloalkenyl and Ari, wherein such Ri and R7 are independently unsubstituted or substituted with one or more substituents independently selected from the group consisting of carboxy, C3-CS cycloalkyl, C5-C7 cycloalkenyl, halo, hydroxy, nitro, trifluoromethyl, cycloalkyl, Linear or branched chain Cg, straight or branched chain C2-C6 alkenyl, C? -Cg alkoxy, C2-Cg alkenyloxy, phenoxy, benzyloxy, amino, and Ar2; R2 is selected from the group consisting of hydrogen, straight or branched chain C1-C9 alkyl, straight or branched chain C2-Cg alkenyl, C3-C8 cycloalkyl, C5-C7 cycloalkenyl and Ari, wherein such R2 is substituted or unsubstituted with one or more substituents independently selected from the group consisting of carboxy, C3-C8 cycloalkyl, C5-C7 cycloalkenyl, halo, hydroxy, nitro, trifluoromethyl, straight or branched chain Ci-Ce alkyl, straight or branched chain C2-C6 alkenyl, Ci-Ce alkoxy, C2-C6 alkenyloxy, phenoxy, benzyloxy, amino, and Ar2; R3 and R4 are independently selected from the group consisting of hydrogen, carboxy, straight or branched chain Ci-Cg alkyl, straight or branched chain C2-Cg alkenyl, C3-C8 cycloalkyl, Cr cycloalkenyl, -C7, and Ari, with the proviso that both R3 and R are not hydrogen; wherein such R3 and R4 are independently unsubstituted or substituted with one or more substituents independently selected from the group consisting of carboxy, C3-C8 cycloalkyl, C5-C7 cycloalkenyl, halo, hydroxy, nitro, trifluoromethyl, Cj-alkyl C, straight or branched chain, straight or branched chain C2-C6 alkenyl, C6-C6 alkoxy, C2-C6 alkenyloxy, phenoxy, benzyloxy, amino, and Ar2; R5 and R6 are independently selected from the group consisting of hydrogen, straight or branched chain Ci-Cß alkyl, straight or branched chain C2-C6 alkenyl, C3-C8 cycloalkyl, C5-C7 cycloalkenyl, Ari, and halo; Ari and Ar2 are independently 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 such Arx and Ar2 are independently unsubstituted or substituted with one or more substituents independently selected from the group consisting of halo, hydroxy, nitro, trifluoromethyl, alkyl of straight or branched chain Cj-Cß, straight or branched chain C2-C6 alkenyl, Ci-Cβ alkoxy, C2-Ce alkenyloxy, phenoxy, benzyloxy, and amino. 78. The pharmaceutical composition according to claim 77, characterized in that: R4 is hydrogen; and R3 is substituted with one or more substituents independently selected from the group consisting of carboxy, Ci-Cß alkoxy, C2-C0 alkenyloxy, phenoxy, and benzyloxy. 79. The pharmaceutical composition according to claim 78, characterized in that the prodrug is selected from the group consisting of: 2- [(benzylmethoxyphosphinyl) methyl] pentanedioic acid;

2- [(benzyloxyethoxyphosphyl) methyl] pentanedioic acid; 2- [(benzylpropoxyphosphinyl) methyl] pentanedioic acid; 2- [(benzylacetoxyphosphyl) methyl] pentanedioic acid; 2- [(benzylbenzyloxyphosphinyl) methyl] pentanedioic acid; 2- [(Benzyl (1-oxopropoxy) methoxyphosphinyl) methyl] pentanedioic acid; 2- [(pentaf1uorobenzylmethoxyphosphinyl) methyl pentanedioic acid; 2- [(pentafluorobenzyl-ethoxy-phosphinyl) -methyl] -pentanedioic acid; 2- [(pentafluorobenzylopropoxyphosphinyl) methyl] pentanedioic acid; 2- [(pentafluorobenzylcoxethoxyphosphinyl) methyl] pentanedioic acid; 2- [(pentafluorobenzyl (1-oxo-propoxy) phosphinyl) methyl] pentandioic; and the pharmaceutically acceptable salts and hydrates thereof. 80. The pharmaceutical composition according to claim 70, characterized in that the amount of the prodrug is effective to treat an abnormality of glutamate in an animal. 81. The pharmaceutical composition according to claim 70, characterized in that the amount of the prodrug is effective to effect neuronal activity in an animal. 82. The pharmaceutical composition according to claim 70, characterized in that the amount of the prodrug is effective to treat a compulsive disorder in an animal. 83. The pharmaceutical composition according to claim 70, characterized in that the amount of the prodrug is effective to treat a disease of the prostate in an animal.