LV12253B

LV12253B - Naaladāzes inhibitori un to pielietojums vēža ārstēšanai

Info

Publication number: LV12253B
Application number: LVP-98-279A
Authority: LV
Inventors: Barbara S. Slusher; Paul F. Jackson; Kevin L. Tays; Keith M. Maclin
Original assignee: Guilford Pharmaceuticals Inc.
Priority date: 1996-06-17
Filing date: 1999-02-11
Publication date: 2000-01-20
Also published as: ZA977087B; US6011021A; NO985652D0; CA2257433A1; CN1221346A; NO985652L; LV12253A; WO1997048409A1; BR9709819A; EP0954295A1; PL330782A1

Description

NAALADASE INHIBITORS AND THEIR USE FOR TREATING CANCER

RELATED APPLICATIONS

This application is a continuation-in-part (CIP) of U.S. patent application serial number 08/665,775, filed June 17, 1996, entitled Methods of Cancer Treatment Using NAALADase Inhibitors.

BACKGROUND OF THE INVENTION

1· Field of the Invention

The present invention relates to novel methods of treating cancer, preventing tumor celi growth, inhibiting prostate tumor celi growth, and inhibiting NAALADase enzyme activity, by administering an effective amount of a NAALADase inhibitor.

2. Deseription of the Prior Art

Prostate Cancer

Prostate cancer is the leading form of cancer and the second leading cause of death from cancer 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 by prostate cancer.

The incidence rāte of prostate cancer increased 65% between 1980 and 1990, and will continue to rise with improved screening tests and longer life expectancies. While most men used to die of other illnesses before prostate cancer had a chance to develop, higher prostate cancer mortality rātes are expected as men live longer and the disease has more time to progress.

-2Ιη 1993, the molecular cloning of Prostate Specific Membrane Antigen (PSMA) was reported as a potential prostate carcinoma marker and hypothesized to serve as a target for imaging and cytotoxic treatment modalities for prostate cancer. PSMA antibodies, particularly indium-111 labelled and tritium labelled PSMA antibodies, have been described and examined clinically for the diagnosis and treatment of prostate cancer. PSMA is expressed in prostatic ductal epithelium and is present in seminal plasma, prostatic fluid and urine. In 1996, it was found that the expression of PSMA cDNA confers the activity of NAALADase.

NAALADase Inhibitors

NAAG and NAALADase have been implicated in several human and animal pathological conditions relating to glutamate abnormalities and neurotoxicity. For example, it has been demonstrated that intra-hippocampal injections of NAAG elicit prolonged seizure activity. More recently, it vvas reported that rats genetically prone to epileptic seizures have a persistent increase in their basai Ievel of NAALADase activity. These observations lend support the hypothesis that increased availability of synaptic glutamate elevates seizure susceptibilicy, and suggest that NAALADase inhibitors may provide anti-epileptic activity.

NAAG and NAALADase have also been implicated in the pathogenesis of ALS and in the pathologically similar animal disease called Hereditary Canine Spinal Muscular Atrophy (HCSMA) . It has been shovvn that concentrations of NAAG and its metabolices -- NAA, glutamate and aspartate -- are

-3elevated two- to three-fold in the cerebrospinal fluid of ALS patients and HCSMA degs. Additionally, NAALADase activity is significantly increased (two- to three-fold) in post-mortem spinal cord tissue from ALS patients and HCSMA dogs. As such, NAALADase inhibitors might be clinically useful in curbing the progression of ALS if an increased metabolism of NAAG is responsible for the alterations of CSF Ievels of these acidic amino acids and peptides.

Abnormalities in NAAG Ievels and NAALADase activity have also been documented in post-mertem schizophrenic brain, specifically in the prefrontal and limbic brain reģions.

The findings described above suggest that NAALADase inhibitors could be useful in treating glutamate abnormalities. However, the present invention is d.irected to the surprising and unexpected discovery that the novel compounds of the present invention are not only effective NAALADase inhibitors but are effective in treating prostate diseases, particularly prostate cancer. Although the cancer data relate to prostate cancer celis, NAALADase inhibitors are expected to be equally effective in treating cancer of other tissues where NAALADase enzyme reside, such as the brain, kidnev and testis.

While a few NAALADase inhibitors have been identified, they have only been used in non-clinical research. Examples of such inhibitors include general metallopeptidase inhibitors such as o-phenanthroline, mētai chelators such as EGTA and EDTA, and peptide analogs such as guisoualic acid and β-NAAG. Accordcngly, a need exists for more NAALADase inhibitors co be

-4identified and, particularly, for the treatment of prostate diseases such as prostate cancer.

SUMMARY OF THE INVENTION

The present invention is directed to novel methods for treating cancer, preventing tumor celi growth, inhibiting prostate tumor celi growth, and inhibiting NAALADase enzyme activity, in an animal, comprising administering an effective amount of a NAALADase inhibitor.

Preferred NAALADase inhibitors include compounds of formula I:

OH vvherein

Rj is hydrogen, C,-C₉ straight or branched chain alkyl, C₂-C₉ straight or branched chain alkenyl group, C₃-C₉cycloalkyl, C_s-C₇ cycloalkenyl, or Ar,;

X is CH₂, 0, or N; and

R₂ is C,-C₉ straight or branched chain alkyl, C₂-C₉straight or branched chain alkenyl group, C₃-C_acycloalkyl, C_s-C₇ cycloalkenyl, or Ar., vvherein said alkyl, alkenyl, cycloalkyl, cycloalkenyl or aryl groups may be optionally substituted vvith carboxylic acid.

-5Preferably, the compound of formula I is present in an amount that is effective for inhibiting NAALADase enzyme activity, or treating a prostate disease in an animal.

The present invention further relates to a method of inhibiting NAALADase enzyme activity in an animal, comprising administering an effective amount of the compound of formula I to said animal.

BRIEF DESCRIPTION OF THE FIGURĒS

FIG. 1 is a bar graph plotting the growth of the prostate cancer celi line, LNCAP, against various concentrations of quisqualic acid, a NAALADase Inhibitor. FIG. 1 shows the effect of 7-day treatment with quisqualate on the growth of LNCAP celis. Concentrations ranging from 10 nM to 1 μΜ of quisqualate show a sharp dose-dependent decrease of LNCAP celi proliferation as indicated by the significant decrease in the incorporation of [3H]thymidine.

FIG. 2 is a bar graph plotting the growth of the prostate cancer celi line, LNCAP, against various concentrations of 2(phosphonomethyl}pentanedioic acid, a NAALADase Inhibitor.

FIG. 2 shows the effect of 7-day treatment vvith 2(phosphonomethyl)pentanedioic acid on the growth of LNCAP celis. Concentrations ranging from 100 pM to 10 nM of 2(phosphonomethyl)pentanedioic acid show a sharp dose-dependent decrease of LNCAP celi proliferation as indicated by the significant decrease in the incorporation of [3H]thymidine.

FIG. 3 is a line graph of the response of LNCAP human

-6prostate tumors to daily treatment with 2(phosphonomethvl) pentanedioic acid. Mean of individual tumor volumes are plctted as a function of time after the start of treatment. Error bars represent the SEM. Treatment with 25 (phosphonometh’/I) pentanedioic acid for six weeks resulted in statistically significant difference between both the control group and animals given daily injections of drug (p=0.04), and the control group and animals implanted with polymer (p=0.02).

FIG. 4 is a line graph plotting the survival percentage 10 of animals treated with injections against the number of days.

FIG. 4 shows the higher mean survival percentage of animals injected with 2 -(phosphonomethyl)pentanedioic acid mixed with polymer as compared to those animals only receiving intratumoral injections of 2-(phosphonomethyl)pentanedioic 15 acid or a vehicle control. The graph shows that 88% of the animals treated with polymer were alive after 72 days, and those animals had small tumors.

FIG. 5 is a line graph plotting tumor growth against days following rat dunning celi injections. Celis were injected, over a period of 84 days, with various dosages of 2(phosphonomethvl)pentanedioic acid and a control vehicle.

FIG. 5 shows that tumor growth slowed as a function of 2(phosphonometr.vl) pentanedioic acid dosage.

FIG. 6 is a line graph of the response of R3327 rat prostate tumors to daily treatment with 2[ [ (phenylmethyl)hydroxyphosphinyl]methyl]pentanedioic acid. Mean of individual tumor volumes expressed relative to the volume at the start of treatment (V/V_o) are plotted as a

-7function of time. Treatment with 2[[ (phenylmethyl) hydroxyphosphinyl]methyl] pentanedioic acid for 2.5 weeks resulted in a statistically significant difference betvveen the control group and animals given daily injections of 1 μ<3 of drug (p=0.02).

DETAILED DESCRIPTION OF THE INVENTION

Definitions

Compound 3 refers to 2-(phosphonomethyl)pentanedioic acid, a NAALADase inhibitor.

Inhibicion, in the context of enzymes, refers to reversible enzyme inhibition such as competitive, uncompetitive and non-competitive inhibition. Competitive, uncompetitive and non-competitive inhibition can be distinguished by the effects of an inhibitor on the reaction kinetics of an enzyme. Competitive inhibition occurs vvhen the inhibitor combines reversibly with the enzyme in such a way that it competes with a normai substrate for binding at the active site. The affinity between the inhibitor and the enzyme may be measured by the inhibitor constant, K_IZ which is defined as:

[E] [I] _K. ₌ -----[EI ] wherein [E] is the concentration of the enzyme, [I] is the concentration of the inhibitor, and [EI] is the concentration of the enzyme-inhibitor complex formed by the reaction of the enzyme vvith the inhibitor. Unless othervvise specified, K. as

-8used 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 which is recuired to cause a 50% inhibition of the target enzyme.

The term inhibition, in the context of tumor growth or tumor celi growth, may be assessed by aelayed appearance of primary or secondary tumors, slowed deveiopment of primary or secondarv tumors, decreased occurrence of primary or secondary tumors, slowed or decreased severity of secondary effects of disease, arrested tumor growth and regression of tumors, among others. In the extreme, complete inhibition, is referred to herein as prevention.

NAAG’’ refers to N-acetyl-aspartyl-glutamate, an importānt peptide component of the brain, with Ievels comparable to the major inhibitor neurotransmitter gammaaminobutyric acid (GABA) . NAAG is neuror.-specif ic, present in synaptic vesicles and released upon neuronal stimulation in several systems presumed to be glutamatergic. Studies suggest that NAAG may funetion as a neurotransmitter and/or neuromodulator in the Central nervous system, or as a precursor of the neurotransmitter glutamate.

NAALADase refers to N-acetyIated α-linked acidic dipeptidase, a membrane-bound metallopeptidase which catabolizes NAAG to N-acetylaspartate (NAA) and glutamate:

-9Catabolism of NAAG by NAALADase

NAALADase shows a high affinity for NAAG with a Km of 540 nM. If NAAG is a bioactive peptiae, then NAALADase may serve to inactivate NAAG'S synaptic action. Alternatively, if NAAG functions as a precursor for glutamate, the primary function of NAALADase may be to regulate synaptic glutamate availability.

Pharmaceutically acceptable salt refers to a salt of the inventive compounds which possesses the desired pharmacological activity and which is neither biolog.ically nor otherwise undesirable. The salt can be formed with inorganic acids such as acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate butyrate, citrate, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptanoate, glycerophosphate, hemisulfate heptanoate, hexanoate, hydro20 chloride hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, oxalate, thiocyanate, tosylate and undecanoate. Examples of a base salt include ammonium salts, alkali mētai

-10salts such as sodium and potassium salts, alkaline earth mētai salts such as calcium and magnesium salts, salts vvith organic bases such as dicyclohexylamine salts, N-methyl-D-glucamine, and salts vvith amino acids such as arginine and lysine. The basie nitrogen-eontaining groups can be quarternized with aģents including lovver alkyl halides such as methyl, ethyl, propyl and butyl chlorides, bromides and iodides; dialkyl sulfātes such as dimethyl, diethyl, dibutyl and diamvl sulfātes; long chain halides such as decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides; and aralkyl halides such as benzyl and phenethyl bromides.

The term prevention, in relation to tumor grovvth or tumor celi grovvth, means no tumor or tumor celi grovvth if none had occurred, no further tumor or tumor celi grovvth if there had already been grovvth.

The term prostate disease relates to prostate cancer such as adenocarcinoma or metastatic cancers, conditions characterized by abnormal grovvth of prostatic epithelial celis such as benign prostatic hyperplasia, and other conditions requiring treatment by the compounds of the present invention.

PSA refers to Prostate Specific Antigen, a vvell knovvn prostate cancer marker. It is a protein produced by prostate celis and is frequently present at elevated Ievels in the blood of mer. vvith prostate cancer. PSA correlates vvith tumor burden, serves as an indicator of metastatic involvement, and provides a parameter for follovving a prostate cancer patient’s response to surgery, irradiation and androgen replacement therapy.

-11PSMA refers to Prostate Specific Membrane Antigen, a potential prostate carcinoma marker that has been hypothesized to serve as a target for imaging and cytotoxic treatment modalities for prostate cancer. PSMA is expressed in prostatic ductal epithelium and is present in seminal plasma, prostatic fluid and urine. It has been found that the expression of PSMA cDNA confers the activity of NAALADase.

The term treatment refers to any process, action, application, therapy, or the like, wherein an anirnal, including a human being, is subject to medical aid vvith the object of improving the anirnal's condition, directly or indirectly.

Preferred NAALADase Inhibitors of the Present Invention

The present invention relates to a compound of formula I:

'Ϊ ⁸² ļ ^^xX'^X^'COOH OH

I or a pharmaceutically acceptable salt, hydrate, or a mixture thereof, wherein:

R_: is hydrogen, C\-C₉ straight or branched chain alkyl,

C,-C₉ straight or branched chain alkenyl group, C₃-C₈cycloalkyl, C_s-C, cycloalkenyl, or Ar,.;

X is CHj, 0, or NR_l( vvhere R₃ is defined above; and R_; is C_x-C₉ straight or branched chain alkyl, C_a-C₉ straight or branched chain alkenyl group, C₃-C₈

-12cycloalkyl, C_s-C₇ cycloalkenyl, or Ar_1? vvherein said alkyl, alkenyl, cycloalkyl, cycloalkenyl or aryl group may be optionally substituted vvith carboxylic acid.

The present invention also contemplates that said alkyl, alkenyl, cycloalkyl, cycloalkenyl or aryl groups may be optionally substituted vvith C₃-C_a cycloalkyl, C₃ or C₅cycloalkyl, C_s-C₇ cycloalkenyl, C₃-C₄ alkyl, C,-C₄ alkenyl, halo, hydroxy, carboxy, nitro, trifluoromethvl, C_x-C_e straight or branched chain alkyl or alkenyl, C₃-C₄ alkoxy, C₃-C₄ alkenyloxy, phenoxy, benzyloxy, amino, or Ar₃, and vvhere Ar. is selected from the group consisting of l-naphthyl, 2-naphthyl, 2indolyl, 3-indolyl, 4-indolyl, 2-furyl, 3-furyl, tetrahydrofuranyl, 2-thienyl, 3-thienyl, 4-thienyl, 2-, 3-, or

4-pyridyl, or phenyl, having one to five substituents vvhich are independently selected from the group consisting of hydrogen, halo, hydroxy, carboxy, nitro, trifluoromethyl, C₃-C_sstraight or branched alkyl or alkenyl, C,-C₄ alkoxy or C_L-C₄alkenyloxy, phenoxy, benzyloxy, and amino; or pharmaceutically acceptable salts, hydrates, or mixtures thereof.

In a preferred embodiment, the compound is selected from the group of formula II:

OH vvherein

R_x is hydrogen, C₃-C₉ straight or branched chain alkyl,

-13C₂-C₉ straight or branched chain alkenyl group, C₃-C₈cycloalkyl, C_s-C₇ cycloalkenyl, or Ar_x; and

R₃ is C^Cj straight or branched chain alkyl, C₂-C₉straight or branched chain alkenyl group, C₃-C₈cycloalkyl, C_s-C₇ cycloalkenyl, or Ar_lz vvherein said alkyl, alkenyl, cycloalkyl, cycloalkenyl or aryl group may be optionally substituted vvith carboxylic acid.

In another preferred embodiment, the R groups are either straight or branched aliphatic substituents or carbocyclic substituents illustrated by the compounds selected from the group of formula II:

vvherein

Ri is hydrogen, C^-Cg straight or branched chain alkyl, C₂-C₉ straight or branched chain alkenyl group, C₃-C₈cycloalkyl, C_s-C₇ cycloalkenyl, l-naphthyl, 2naphthyl, or phenyl; and

R₂ is C_x-C₉ straight or branched chain alkyl, C₂-C₉straight or branched chain alkenyl group, C₃-C₈cycloalkyl, C₅-C₇ cycloalkenyl, l-naphthyl, 2naphthyl, or phenyl, vvherein said alkyl, alkenyl, cycloalkyl, cycloalkenyl, l-naphthyl, 2-naphchyl, or

-14phenyl group may be optionally substituted with carboxylic acid.

Especially preferred methods utilizē compounds wherein R_x5 is either a straight or branched aliphatic group or a carbocyclic group, R₂ is ethyl which is substituted with a carboxylic acid, and X is CH, are selected from the group consisting of:

-[[methylhydroxyphosphinyl]methyl]pentanedioic acid;

2-[[ethylhydroxyphosphinyl]methyl]pentanedioic acid;

2-[[propylhydroxyphosphinyl]methyl]pentanedioic acid;

2- [ [butylhyaroxyphosphinyl]methyl]pentanedioic acid;

2-[[cyclohexylhydroxyphosphinyl]methyl]pentanedioic acid;

- [[(cyclohexyl)methylhydroxyphosphinyl]methyl]pentanedioic acid;

2-[[phenylhydroxyphosphinyl]methyl]pentanedioic acid;

2-[[benzylhydroxypnosphinyl]methyl]pentanedioic acid;

2-[[phenylethylhydroxyphosphinyl]methyl]pentanedioic acid;

2- [[phenylpropylhydroxyphosphinyl]methyl]pentanedioic acid;

2-[[phenylbutylhydroxypnosphinyl]methyl]pentanedioic acid;

2-[[(4-methylbenzyl)hydroxyphosphinyl]methyl]pentanedioic acid;

2- [[(4-fluorobenzyl)hydroxyphosphinyl]methyljpentanedioic acid;

2-[[(2-fluorobenzyl)hydroxyphosphinyl]methyl]pentanedioic acid;

2- ([(pentaflucrobenzyl)hydroxyphosphinyl]methyl]pentanedioic acid;

-152-[[(methoxybenzyl)hydroxyphosphinyl]methyl]pentanedioic acid;

2-[[(4-fluorophenyl)hydroxypnosphinyl]methyl]pentanedioic acid;

- [ [ ( (hydroxy) phenylmethyl) hydroxyphosphinyl] methyl] pentanedioic acid;

-[[(3-methylbenzyl)hydroxyphosphinyl]methyl]pentanedioic acid;

2-(phosphonomethyl)pentanedioic acid;

2- [ ((310 trifIuoromethylbenzyl)hydroxyphosphinyl] methyl]pentanedioic acid;

2-[[(2, 3, 4 - trimethoxyphenyl) hydroxyphosphinyl] methyl] pentanedioic acid;

2-[[(1-naphthyl)hydroxyphosphinyl]methyl] pentanedioic acid;

2-[[(2-naphthyl)hydroxyphosphinyl]methyl] pentanedioic acid;

- [ [ (1 -naphthyl) methylhydroxyphosphinyl] methvl J pentanedioic acid;

2-[[(2-naphthyl)methylhydroxyphosphinyi] methyl·]pentanedioic acid;

2- [ ( (l-naphthyl) ethylhydroxyphosphinyl] methyl] pentanedioic acid;

- [ [ (2-naphthyl) ethylhydroxyphosphinyl] methyl] pentanedioic acid;

- [ [ (l-naphthyl) propylhydroxyphosphinyl] methyl] pentanedioic 25 acid;

2- [ ((2-naphthyl) propylhydroxyphosphinyl ] methyl] pentanedioic acid;

- [ [ (l-naphthyl) butylhydroxyphosphinyl]methyl] pentanedioic

-16acid;

2-[[(2-naphthyl)butylhydroxyphosphinyl]methyl]pentanedioic acid; and

2-[[(phenylprop-2-enyl)hydroxyphosphinylj methyl]pentanedioic acid.

Especially preferred methods utilizē compounds wherein R, is either a straight or branched aliphatic group or a carbocyclic group, R₂ is ethyl which is substituted with a carboxylic acid, and X is CH₂ are selected from the group consisting of:

2-[(benzylhydroxyphosphinyl)methyl]pentanedioic 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)hydroxyphosphinyl]methyl]pentanedioic acid;

2-[(methylhydroxyphosphinyl)methyl]pentanedioic acid;

-[(phenylethylhydroxyphosphinyl)methyl]pentanedioic acid;

2-[[{4-methylbenzyl)hydroxyphosphiny1]methyl]pentanedioic acid;

2-[[(4-fluorobenzyl)hydroxyphosphinyl]methyl]pentanedioic acid;

2-[[(4-methoxybenzyl)hydroxyphosphinyl]methyl]pentanedioic

-17acid;

2-[[(2-fluorobenzyl)hydroxyphosphinyl]methyl]pentanedioic acid;

- [ [ (pentafluorobenzyl) hydroxyphosphinyl] methyl] pentanedioic acid;

-(phosphonomethyl)pentanedioic acid; and

2-[[(3trifluoromethylbenzyl)hydroxyphosphinyl] methyl]pentanedioic acid.

Especially preferred methods utilizē compounds wherein R_xis a straight or branched aliphatic group or a carbocyclic group, R₂ is phenyl, and X is CH₂ are selected from the group consisting of:

3-(methylhydroxyphosphinyl)-2-phenylpropanoic acid;

3- (ethylhydroxyphosphinyl)-2-phenylpropanoic acid;

3-(propylhydroxyphosphinyl)-2-phenylpropanoic acid;

3-(butylhyaroxyphosphinyl)-2-phenylpropanoic acid;

3-(cyclohexylhydroxypnosphinyl)-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-phenylpropanoic acid;

3-(phenylbutylhydroxvphosphinyl)-2-phenylpropanoic acid;

3-[(2, 3, 4-trimethoxyphenyl)-3-hydroxyphosphinyl]-2phenylpropanoic acid;

-183-[(l-naphthyl)hydroxyphospninyl]-2-phenylpropanoic acid;

3- [ (2-naph.thyl) hydroxyphosphinyl] -2-phenylpropanoic acid;

3-[(l-naphchyl)methylhydroxyphosphinyl]-2-phenylpropanoic acid;

3-[ <2-naphthyl) methylhydroxyphosphinyl]-2-phenylpropanoic acid;

3-[(l-naphthyl)ethylhydroxyphosphinyl]-2-phenylpropanoic acid; 3-[(2-naphthyl)ethylhydroxyphosphinyl]-2-phenylpropanoic acid; 3-[(1-naphthyl)propylhydroxyphosphinyl]-2-phenylpropanoic acid;

3-[ (2-naphthyl) propylnydroxyphosphinyl]-2-phenylpropanoic acid;

3-[(1-naphthyl)butylhydroxyphosphinyl]-2-phenylpropanoic acid; 3-[(2-naphthyl)butylhydroxyphosphinyl]-2-phenylpropanoic acid;

and

3-[phenylprop-2-enylhydroxyphosphinyl]-2-phenylpropanoic acid.

Although not limited to any cr.e species, a highly preferred species vvhere R_x is a straight or branched aliphatic group or a carbocyclic group, R₂ is ethyl vvhich is substituted vvith carboxylic acid, and X is CH₂ is

- [ [benzylhydroxyphosphinyl ] methyl ] pentanedioic acid.

Other preferred compounds of the present invention are selected from the group consisting of:

hydroxyphosphinyl derivatives vvherein X is CH₂, R₂ is a straight or branched aliphatic group .or a carbocyclic group, and R, is an C₂-C_a alkyl or alkenyl chain vvhich is substituted

-19with a carboxylic acid. Exemplary species include:

2- [ (methylhydroxyphosphinyl) methyl] hexanedioic acid; 2- [ (benzylhydroxyphosphinyl) methyl] hexanedioic acid;

- [ (methylhydroxyphosphinyl) methyl] heptanedioic acid; 2- [ (benzylhydroxyphosphinyl) methyl] heptanedioic acid; 2- [ (methylhydroxyphosphinyl)methyl] octanedioic acid; 2- [ (benzylhydroxyphosphinyl) methyl] octanedioic acid;

- [ (methylhydroxyphosphinyl) methyl] nonanedioic acid; 2- [ (benzylhydroxyphosphinyl)methyl] nonanedioic acid; 2- [ (methylhydroxyphosphinyl) methyl] decanedioic acid; 2- E (benzylhydroxyphosphinyl) methyl] decanedioic acid.

and

Other preferred compounds are selected from the group consisting of:

hydroxyphosphinyl derivatives wherein X is CH₂, R, is benzyl, and R₂ is a straight or branched aliphatic group or a carbocyclic group. Exemplary species include:

3- (benzylhydroxyphosphinyl) -2-methylpropanoic acid;

3- (benzylhydroxyphosphinyl) -2-ethylpropanoic acid;

3- (benzvlhydroxyphosphinyl) -2-propylpropanoic acid;

3- (benzylhydroxyphosphinyl) -2-butylpropanoic acid;

3- (benzylhydroxyphosphinyl) -2-cyclohexylpropanoic acid;

3- <benzylhydroxyphosphinyl) - 2- (cyclohexyl)methylpropanoic acid;

3- (benzvlhydroxyphosphinyl) -2-phenylpropanoic acid;

3- (benzvlhydroxyphosphinyl) -2-benzylpropanoic acid;

3- (benzylhydroxyphosphinyl) -2-phenylethylpropanoic acid;

3- (benzylhydroxyphospninyl)-2-phenvlpropylpropanoic acid;

-203 - (benzylhydroxyphosphinyl) -2-phenylbutylpropanoic acid;

3-(benzylhydroxyphosphinyl) -2-(2, 3, 4-trimethoxyphenyl) propanoic acid;

3- (benzylhydroxyphosphinyl) -2- (l-naphthyl)propanoic acid;

- (benzylhydroxyphosphinyl) -2- (2-naphthyl) propanoic acid;

3- (benzylhydroxyphosphinyl) -2- (l-naphthyl) methylpropanoic acid;

3- (benzylhydroxyphosphinyl)-2-(2-naphthyl)methylpropanoic acid;

3- (benzylhydroxyphosphinyl) -2- (l-naphthyl) ethylpropanoic acid; 3- (benzylhydroxyphosphinyl) -2- (2-naphthyl) ethylpropanoic acid; 3- (benzylhydroxyphosphinyl) - 2- (l-naphthyl) propylpropanoic acid;

3- (benzylhydroxyphosphinyl)-2-(2-naphthyl)propylpropanoic acid;

3- (benzylhydroxyphosphinyl) - 2- (l-naphthyl)butylpropanoic acid; 3- (benzylhydroxyphosphinyl) -2- (2-naph.th.yi) butylpropanoic acid; and

3- (benzylhydroxyphosphinyl)-2-phenylprop-2-enylpropanoic acid.

Especially preferred methods use compounds wherein R_: is said alkyl, alkenyl, cycloalkyl, or aryl group vvhich is substituted vvith a heterocyclic group, R₂ is ethyl vvhich is substituted vvith a carboxylic acid, and X is CH₂ are seiected from the group consisting of:

2- [ [ (2-pyridyl)methylhydroxyphosphinyl]methyl] pentanedioic acid;

2- [ [ (3 -pyridyl) methylhydroxyphosphinyl ] methyl ] pentanedioic

-21acid;

2-[[(4-pyridyl)methylhydroxyphosphinyl]methyl]pentanedioic acid;

2-[[(3-pyridyl)ethylhydroxyphosphinyl]methyl]pentanedioic acid;

- ([ (3 -pyridyl) propyl·hydroxyphosph.inyl] methyl] pentanedioic acid;

2-[[(tetrahydrofuranyl)methylhydroxyphosphinyl]methyl] pentanedioic acid;

-[[(tetrahydrofuranyl)ethylhydroxyphosphinyl]methyl] pentanedioic acid;

2-[[(tetrahydrofuranyl)propylhydroxyphosphinyl]methyl] pentanedioic acid;

2-[[<2-indolyl)methylhydroxyphosphinyl]methyl]pentanedioic acid;

2-[[(3-indolyl)methylhydroxyphosphinyl]methyl]pentanedioic acid;

2-([(4-indolyl)methylhydroxyphosphinyl]methyl]pentanedioic acid;

2-[[(3-indolyl)ethylhydroxyphosphinyl]methyl]pentanedioic acid;

- [[(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

-22acid;

- ([(3 -thienyl)ethylhydroxyphosphinyl]methyl]pentanedioic acid; and

2-(((3 -thienyl)propylhydroxyphosphinyl]methyl]pentanedioic acid.

Especially preferred methods use compounds wherein Rļ is said alkyl, alkenyl, cycloalkyl, or aryl group which is substituted with a heterocyclic group, R₂ is phenyl, and X is CH₂ are selected from the group consisting of:

3-((2-pyridyl)methylhydroxyphosphinyl]-2-phenylpropanoic acid; 3-((3-pyridyl)methylhydroxyphosphinyl]-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-phenyl propanoic acid;

3-[(tetrahydrofuranyl)ethylhydroxyphosphinyl]-2-phenyl propanoic acid;

3-[(tetrahydrofuranyl)propylhvdroxyphosphinyi]-2-phenyl propanoic 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)methyihydroxyphosphinyl]-2-phenylpropanoic acid; 3-((3-thienyl)methylhydroxyphosphinyl]-2-phenylpropanoic acid;

-233- [ (4 -thienyl)methylhydroxyphosphinyl] -2-phenylpropanoic acid; 3- ((3-thienyl)ethylhydroxyphosphinyl]-2-phenylpropanoic acid; and

3-[(3-thienyl)propylhydroxyphosphinyl]-2-phenylpropanoic acid.

Especially preferred methods use compounds vvherein R, is benzyl, R₃ is said alkyl, alkenyl, cycloalkyl, or aryl group vvhich is substituted vvith a heterocyclic group, and X is CH₂are selected from the group consisting of:

3-(benzylhydroxvphosphinyl)-2-(2-pyridyl)methylpropanoic acid; 3-(benzylhydroxyphosphinyl)-2-(3-pyridyl)methylpropanoic acid; 3-(benzylhydroxyphosphinyl)-2-(4-pyridyl)methylpropanoic acid; 3 - (ber.zylhydroxyphosphinyl) -2- (3-pyridyl) ethylpropanoic acid; 3- (benzylhydroxyphosphinyl) -2- (3-pyridyl)propylpropanoic acid; 3-(benzylhydroxyphosphinyl)-2-(tetrahydrofuranyl) methyl propanoic acid;

3-(benzylhydroxyphosphinyl)-2-(tetrahydrofuranyl)ethyl propanoic acid;

3-(benzylhydroxyphosphinyl)-2-(tetrahydrofuranyl)propyl propanoic acid;

3-(benzylhydroxyphosphinyl)-2-(2-indolyl)methylpropanoic acid; 3- (ber.zylhydroxyphosphinyl) -2- (3-indolyl) methylpropanoic acid; 3- (benzylhydroxvphosphinyl) -2- (4-indolvl)methylpropanoic acid; 3- (ber.zylhydroxyphosphinyl) -2- (3-indolyl) ethylpropanoic acid; 3- (ber.zylhydroxyphosphinyl) -2- (3-indolyl)propylpropanoic acid; 3- (ber.zylhydroxyphosphinyl) -2- (2-thienyl)methylpropanoic acid; 3-(berzylhvdroxyphosphinyl)-2-(3-thienyl)methylpropanoic acid; 3-(benzylnydroxyphosphinyl)-2-(4-thienyl)methylpropanoic acid;

-243- (benzylhydroxyphosphinyl) -2- (3-thienyl)ethylpropanoic acid; and

3- (benzylhydroxyphosphinyl) -2- (3-thienyl)propylpropanoic acid.

In another preferred embodiment, the R groups are heterocyclic substituents illustrated by the compounds selected from the group having formula II:

II wherein

R₂ is Ar₁₍· and

R₂ is Cj —Ca straight or branched chain alkyl, C₂-C, straight or branched chain alkenyl group, C₃-C₈cycloalkyl, C₅-C, cycloalkenyl, or Ar_x, wherein said alkyl, alkenyl, cycloalkyl, cycloalkenyl or aryl group may be optionally substituted with carboxylic acid.

Especially preferred methods use compounds wherein Rj is a heterocyclic group, R₂ is ethyl which is substituted with carboxylic acid, and X is CH₂ are selected from the group consisting of:

- [ [ (2-pyridyl) hydroxypnosphinyl] methyl] pentanedioic acid;

2- ([ (3-pyridyl) hydroxyphosphinyl] methyl] pentanedioic acid;

2- [ [ (4-pyridyl) hydroxyphosphinyl] methyl] pentanedioic acid;

-252 - [ [ (tetrahydrofuranyl) hydroxyphosphinyl] methyl] pentanedioic acid;

- [ [ (2-indolyl) hydroxyphosphinyl] methyl] pentanedioic 2- [ [ (3-indolyl) hydroxyphosphinyl] methyl] pentanedioic 2 - [ [ (4-indolyl) hydroxyphosphinyl ] methyl] pentanedioic 2 - [ [ (2-thienyl) hydroxyphosphinyl] methyl]pentanedioic 2 - [ ((3-thienyl) hydroxyphosphinyl] methyl] pentanedioic 2- ([ (4-thienyl) hydroxyphosphinyl] methyl] pentanedioic acid;

acid;

acid; and acid.

Compounds of the present invention vvherein R_x is a heterocyclic group, R₂ is phenyl, and X is CH₂ are selected from the group consisting of:

3-[(2-pyridyl)hydroxyphosphinyl]-2-phenylpropanoic acid;

3-[(3-pyridyl)hydroxyphosphinyl]-2-phenylpropanoic acid;

3-[(4-pyridyl)hydroxyphosphinyl]-2-phenylpropanoic acid;

3-[(tetrahydrofuranyl)hydroxyphosphinyl]-2-phenylpropanoic acid;

3-[(2-indolyl)hydroxyphosphinyl]-2-phenylpropanoic acid;

3-[(3-indolyl)hydroxyphosphinyl]-2-phenvlpropanoic acid;

3-[(4-indolyl)hydroxyphosphinyl]-2-phenylpropanoic acid;

3-((2-thienyl)hydroxyphosphinyl]-2-phenylpropanoic acid;

3-[(3-thienyl)hydroxyphosphinyl]-2-phenylpropanoic acid; and 3-[(4-thienyl)hydroxyphosphinyl]-2-phenylpropanoic acid.

Compounds are also preferably selected from the group of formula II:

R2

COOH

OH

II vvherein

Rj. is hydrogen, C_x-C, straight or branched chain alkyl, C₂-C₉ straight or branched chain alkenyl group, C₃-C₈cycloalkyl, C₅-C, cycloalkenyl, or Ar_r; and

R₂ is Ar, wherein said aryl group may be optionally substituted vvith carboxylic acid.

Particular species vvherein R₂ is heterocyclic may be easily made and used by persons of ordinary skill in the art in accordance vvith the teachings provided herein and knovvn in the art.

Compounds vvherein R_k is is CH, are selected from the 3-(benzylhydrcxyphosphinyl)3-(benzylhydroxvphosphinyl)3-(benzylhydroxyphosphinyl)3-(benzylhydrcxyphosphinyl)acid;

3- (benzylh.ydroxyphosph.inyl) 3-(benzylhydroxyphosphinyl)3-(benzylhydrcxyphosphinyl)3-(benzylhydroxyphosphinyl)3-(benzylhydrcxyphosphinyl)benzyl, R₃ is heterocyclic, and X group consisting of:

-(2-pyridvl)propanoic acid;

-(3-pyridyl)propanoic acid;

-(4-pyridyl)propanoic acid;

-(tetrahydrofuranyl)propanoic

2-(2-indolyl)propanoic acid;

2-(3-indolyl)propanoic acid;

-(4 -indolyl)propanoic acid;

2-(2-thienyl)propanoic acid;

2-(3-thienyl)propanoic acid; and

-273-(benzylhydroxyphosphinyl)-2-(4-thienyl)propanoic acid.

Preferred compounds are also selected from formula III:

^O^^COOH OH

III vvherein

R, is hydroaen, C₁-C₉ straight or branched chain alkvl, C₂-C₉ straight or branched chain alkenyl group, C₃-C₃cycloalkyl, C_s-C₇ cycloalkenyl, or Ar,,· and

Rj is Cļ-C, straight or branched chain alkyl, C₂-C₉10 straight or branched chain alkenvl group, C₃-C₈ cycloalkyl, C_s-C₇ cycloalkenyl, or Ar₁₍ vvherein said alkyl, alkenyl, cycloalkyl, cycloalkenyl or aryl group may be optionally substituted vvith carboxylic acid.

In another preferred embodiment, the R groups are straight or branched or carbocyclic substituents illustrated by the compounds selected from the group of formula III:

vvherein

Ri^O^^COOH

OH

III

-28R_x is hydrogen, C^C, straight or branched chain alkyl, C₂-C_g straight or branched chain alkenyl group, C₃-C₈cycloalkyl, C₅-C₇ cycloalkenyl, l-naphthyi, 2naphthyl, or phenyl; and

R₂ is Cj-Cj straight or branched chain alkyl, C₃-C₉straight or branched chain alkenyl group, C₃-C₈cycloalkyl, C₅-C₇ cycloalkenyl, l-naphthyl, 2naphthyl, or phenyl, wherein said alkyl, alkenyl, cycloalkyl, cycloalkenyl, l-naphthyl, 2-naphthyl, or phenyl group may be optionally substituted vvith carboxylic acid.

Especially preferred compounds of Formula III of the present invention wherein R, is a straight or branched aliphatic group or a carbocyclic group and R₃ is ethvl vvhich is substituted vvith a carboxylic acid are selected from the group consisting of:

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-([phenyletnylhydroxyphosphinyl]oxy]pentanedioic acid;

2-[[phenylpropyihydroxyphosphinyl]oxy]pentanedioic acid;

2-[[phenvlbutylhydroxyphosphinyl]oxy]pentanedioic acid;

-292-[[(4-methylbenzyl)hydroxyphosphinyl}oxy]pentanedioic acid;

- [ [(4-fluorobenzyl)hydroxyphosphinyl]oxy]pentanedioic acid;

2-[[(2-fluorobenzyl)hydroxyphosphinyl] oxy]pentanedioic acid;

- [ [ (pentafluorobenzyl)hydroxyphosphinyl]oxy] pentanedioic acid;

2-[i(methoxybenzyl) hydroxyphosphinyl] oxy]pentanedioic acid;

- [ [(4-fluorophenyl)hydroxyphosphinyl]oxy]pentanedioic acid; 2-((((hydroxy)phenylmethyl)hydroxyphosphinyl]oxy]pentanedioic acid;

2-[[(3-methylbenzyl)hydroxyphosphinyl]oxy]pentanedioic acid;

2-(phosphono)oxy]pentanedioic acid;

2- [ [ (3trifluoromethylbenzyl)hydroxyphosphinyl}oxy]pentanedioic acid; 2-(((2, 3, 4-trimethoxyphenyl)hydroxyphosphinyl]oxy] pentanedioic acid;

- ([ (l-naphthyl) hyaroxyphosphinyl] oxy] pentanedioic acid;

2-[[(2-naphthyl)hydroxyphosphinyl]oxy]pentanedioic acid;

- (((l-naphthyl)methyihydroxyphosphinylļoxy]pentanedioic acid; 2-[[(2-naphthyl) methylhydroxyphosphinyl] oxy] pentanedioic acid;

2-[[(1-naphthyl)ethylhydroxyphosphinyl]oxy]pentanedioic acid;

2-[[(2-naphthyl)ethylhydroxyphosphinyl]oxy]pentanedioic acid;

- ([(1-naphthyl)propylhydroxyphosphinvl]oxy]pentanedioic acid; 2-[[(2-naphthyl)propylhydroxyphosphinyl3oxy]pentanedioic acid; 2-([(l-naphthyl)butylhydroxyphosphinyl]oxy]pentanedioic acid;

2-[[(2-naphthyl)butylhydroxyphosphinyl] oxy]pentanedioic acid;

and

2-([(phenylprop-2-enyl)hydroxyphosphinyl]oxy]pentanedioic acid.

-30Especially preferred compounds of Formula III of the present invention vvherein R_x is a straight or branched aliphatic group or a carbocyclic group and R₂ is ethyl vvhich is substituted vvith a carboxylic acid are selected from the group consisting of:

2- [ (benzylhydroxyphosphinyl) oxy] pentanedioic acid;

- [ (phenylhydroxyphosphinyl) oxy] pentanedioic acid;

2- [ [ ((hydroxy) pnenyltnethyl) hydroxyphosphinyl] oxy] pentanedioic acid;

2- [ (butylhydroxyphosphinvl) oxy] pentanedioic acid;

2- [ [ (3-methylbenzyl)hydroxyphosphinyl] oxy] pentanedioic acid;

2- ((3-phenylpropylhydroxvphosphinyl) oxy] pentanedioic acid;

- [ [ (4 -fluorophenyl) hydroxyphosphinyl] oxy] pentanedioic acid;

- [ (methylhydroxyphosphinyl) oxyl pentanedioic acid;

2- [ (phenylethylhydroxyphosphinyl) oxy] pentanedioic acid;

— C C (4-methylbenzyl) hydroxyphosphinyl] oxylpentanedioic acid;

2- [ [ (4-fluorobenzyl) hydroxyphosphinyl] oxy] pentanedioic acid;

- [ [ (4-methoxybenzyl) hydroxyphosphinyl] oxy] pentanedioic acid;

- [ [ (2-f luorobenzyl) hydroxyphosphinyl] oxy] pentanedioic acid;

- [ [ (pentafluorobenzyl) hydroxyphospninyl] oxyj pentanedioic acid;

2-[(phosphono)cxy]pentanedioic acid; and

2- [[(3trif luoromethylbenzyl) hydroxyphosphinyl} oxy] pentanedioic acid.

Compounds of the present invention vvherein R_t is a straight or branched aliphatic group or a carbocyclic group, R₃is phenyl, and X is oxygen are selected from the group

-31consisting of:

2-[[methylhydroxyphosphinyl]oxy]-2-phenylethanoic acid;

2-[[ethylhydroxyphosphinyl]oxy]-2-phenylethanoic acid;

-[[propylhydroxyphosphinyl]oxy]-2-phenylethanoic acid;

2-[[butylhydroxyphosphinyl]oxy]-2-phenylethanoic acid;

2-[[cyclohexylhydroxyphosphinyl]oxy]-2-phenylethanoic acid;

2- [ [ {cyclohexyl)methylhydroxyphosphinyl] oxy] -2-phenylethanoic acid;

2-[[phenylhydroxyphosphinyl]oxy]-2-phenylethanoic acid;

2-[[benzylhydroxyphosphinyl]oxy]-2-phenylethanoic acid;

2-[[phenylethylhydroxvphosphinyl]oxy]-2-phenylethanoic acid;

2- [ [phenylpropylhydroxyphosphinyl] oxy] -2-phenylethanoic acid; 2- [ [phenylbutylhydroxyphosphinyl]oxy] -2-phenylethanoic acid;

2-[[(2, 3, 4-trimethoxyphenyl)-3-hydroxyphosphinyl]oxy]-215 phenylechanoic acid;

2-[[(l-naphthyl)hydroxyphosphinyl]oxy]-2-phenylethanoic acid;

- [ [(2-naphthyl)hydroxyphosphinyl]oxy] -2-phenylethanoic acid;

- [ E (l-naphthyl) methylhydroxyphosphinyl) ]oxy] -2-phenylethanoic acid;

2 - [ {(2-naphthyl)methylhydroxyphosphinyl] oxy] -2-phenylethanoic acid;

2- [ ( (l-naphthyl) ethylhydroxyphosphinyl] oxy] -2-phenylethanoic acid;

- [ [ (2-naphthyl) ethylhydroxyphosph.in.yl] oxy] -2-phenylethanoic 25 acid;

- [ [ (l-naphthyl)propylhydroxyphosphinyl] oxy] -2-phenylethanoic acid;

- [ [ (2-r.aphthyl) propylhydroxyphosphinyl] oxy] -2-phenylethanoic

-32acid;

- [ [ (l-naphthyl) butylhydroxyph.osph.inyl] oxy] -2-phenylethanoic acid;

2-[[(2-naphthyl)butylhydroxyphosphinyl]oxy]-2-phenylethanoic acid; and

2-[[pnenylprop-2-enylhydroxyphosphinyl]oxy]-2-phenylethanoic acid.

Although not limited to any one particular species, a highly preferred species vvhere is a straight or branched aliphatic group or a carbocyclic group, R, is ethyl vvhich is substituted vvith carboxylic acid, and X is oxygen is 2 -[(benzylhydroxypnosphinyl]oxy]pentanedioic acid.

Other especially preferred compounds of the present invention are selected from the group consisting of: phosphonate derivatives vvherein X is oxygen, R, is a straight or branched aliphatic group or a carbocyclic group, and R₂ is an C₂-C₈ alkyl or alkenvl chain vvhich is substicuted vvith a carboxylic acid. Exemplary species include:

2- ( (met'hylhydroxyphosphinyl) oxy] hexanedioic acid;

2-[(benzylhydroxyphosphinyl)oxy]hexanedioic acid;

2-((methylhydroxyphosphinyl)oxy]heptanedioic acid;

2-[(benzylhydroxyphosphinyl)oxy]heptanedioic acid;

2-[(methylhydroxyphosphinyl)oxy]octanedioic acid;

2-[(benzylhydroxyphosphinyl)oxy]octanedioic acid;

2-[(mechylhydroxyphosphinyl)oxy]nonanedioic acid;

2-[(benzylhydroxyphosphinyl)oxy]nonanedioic acid;

-332-[ (methylhydroxyphosphinyl) oxy] decanedioic acid; and 2- [ (benzylhydroxyphosphinyl) oxy] decanedioic acid.

Other especially preferred compounds are selected from the group consisting of:

phosphonate derivatives wherein X is oxygen, R_x is benzyl, and R₂ is a straight or branched aliphatic group or a carbocyclic group. Exemplary species include:

2-[[benzylhydroxyphosphinyl]oxy]-2-methylethanoic acid;

2- [ [benzylhydroxyphosphinyl] oxy] -2-ethylethanoic acid;

2-[[benzylhydroxyphosphinyl]oxy] -2-propylethanoic acid;

2- f [benzylhydroxyphosphinyl] oxy] -2-butylethanoic acid;

2- [ [benzylhydroxyphosphinyl] oxy] -2-cyclohexylethanoic acid;

2- ( [benzylhydroxyphosphinyl] oxy3 -2- (cyclohexyl) methylethanoic acid;

2- [ [benzylhydroxyphosphinyl] oxy] -2-phenylethanoic acid;

2- [ [benzylhydroxyphosphinyl) oxy] -2-benzylethanoic acid;

2- [ [benzylhydroxvphosphinyl) oxy] -2-phenylethylethanoic acid;

2-[[benzylhydroxyphosphinyl] oxy]-2-phenylpropylethanoic acid; 2-[[benzylhydroxyphosphinyl] oxy]-2-phenylbutylethanoic acid;

- [[benzylhydroxyphosphinyl]oxy]-2-(2, 3, 4trimethoxyphenyl) ethanoic acid;

2- [ [benzylhydroxyphosphinyl] oxy] -2- (l-naphthyl) ethanoic acid; 2- ( [benzylhydroxyphosphinyl] oxy] -2- (2-naphthyl) ethanoic acid; 2- [[benzylhydroxyphosphinyl] oxy] - 2-(l-naphthyl)methylethanoic acxd;

2- ( (benzylhydroxyphosphinyl] oxy] -2- (2-naphchyl) methylethanoic acid;

-342- [ [benzylhydroxyphosphinyl] oxy] -2- (l-naphthyl) ethylethanoic acid;

2- [ [benzylhydroxyphosphinyl] oxy] -2- (2-naphthyl)ethylethanoic acid;

2- [ [benzylhydroxyphosphinyl] oxy) -2- (l-naphthyl)propylethanoic acid;

2- [ [benzylhydroxyphosphinyl] oxy] -2- (2-naphthyl)propylethanoic acid;

2- [ [benzylhydroxyphosphinyl] oxy] -2- (l-naphthyl)butylethanoic acid;

2-[[benzylhydroxyphosphinyl]oxy]-2- (2-naphthyl)butylethanoic acid; and

2- ( (benzylhydroxyphosphinyl]oxy) -2-phenylprop-2-enylethanoic acid.

Especialiy preferred methods utilizē compounds vvherein. R. is said alkyl, alkenyl, cvcloalkyl, or aryl group vvhich is substituted with a heterocyclic group, R_; is ethyl vvhich is substituted vvich a carboxylic acid, and X is oxygen are selected from the group consisting of:

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-[[{tetrahydrcfuranyl)methylhydroxyphosphinyl]oxy] pentanedioic acid;

2-[[(tetrahydrofuranyl)ethylhydroxyphosphinyl]oxy]

-35pentanedioic acid;

2-[[(tetrahydrofuranyl)propylhydroxyphosphinyl]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;

- [ [(3-indolyl)propylhydroxypnosphinyl]oxy]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)ethylhydroxyphosņhinyl]oxy]pentanedioic acid; and

-[[(3 -thienyl)propylhydroxyphosphinyl]oxy]pentanedioic acid.

Especially preferred methods utilizē compounds wherein R_:is said alkyl, alkenyl, cycloalkyl, or arvl group which is substituted with a heterocyclic group, R₂ is phenyl, and X is oxygen are selected from the group consisting of:

2-[[(2-pyridyl)methylhydroxyphosphinyl]oxy]-2-phenylethanoic acid;

2-[[(3-pyridyl)methylhydroxyphosphinyl]oxy]-2-phenylethanoic acid;

2-[[(4-pyridyl)methylhydroxyphosphinyl]oxy]-2-phenylethanoic 25 acid;

2- [ [ (3-pvridvl) ethylhydroxyph.osph.inyl] oxy] -2-phenylethanoic acid;

2-[[(3-pyridyl)propylhydroxyphosphinyl]oxy]-2-phenylethanoic

-36acid;

2-[[(tetrahydrofuranyl)methylhydroxyphosphinyl]oxy]-2-phenyl ethanoic acid;

2-[[(tetrahydrofuranyl)ethylhydroxyphosphinyl]oxy]-2-phenyl 5 ethanoic acid;

- [ [(tetrahydrafuranyl)propylhydroxyphosphinyl]oxy]-2-phenyl ethanoic acid;

2-[[(2-indolyl)methylhydroxyphosphinyljoxy]-2-phenylethanoic acid;

2-[[(3-indolyl)methylhydroxyphosphinyl]oxy]-2-phenylethanoic acid;

2-[[(4-indolyl)methylhydroxyphosphinyl]oxy]-2-phenylethanoic acid;

2-[[(3-indolyl)ethylhydroxyphosphinyl]oxy]-2-phenylethanoic 15 acid;

2-[[(3-indolyl)propylhydroxyphosphinyl]oxy]-2-phenylethanoic acid;

2-[[(2-thienyl)methylhydroxyphosphinyl]oxy]-2-phenylethanoic acid;

0 2-[[(3 -thienyl)methylhydroxyphosphinyl]oxy]-2-phenylethanoic acid;

2-[[(4-thienyl)methylhydroxyphosphinyl]oxy]-2-phenylethanoic acid;

2-([(3-thienyl)ethylhydroxyphosphinyl]oxy]-2-phenylethanoic 25 acid; and

2-[[(3-thienyl)propylhydroxyphosphinyl]oxy]-2-phenylethanoic acid.

-37Especially preferred methods utilizē compounds vvherein Rj. is beņzyl, R₂ is said alkyl, alkenyl, cycloalkyl, or aryl group vvhich is substituted vvith a heterocyclic group, and X is oxygen are selected from the group consisting of:

2-[[benzylhydroxyphosphinyl]oxy]-2-(2-pyridyl)methylethanoic acid;

2-[[benzylhydroxyphosphinyl]oxy]-2-(3-pyridyl)methylethanoic acid;

2- [ [benzylhydroxyphosphinyl]oxy] -2- (4-pyridyl) methylethanoic acid;

2- [ [benzylh.ydroxyphosph.inyl]oxy] -2- (3-pyridyl) ethylethanoic acid;

2-[[benzylhydroxyphosphinyl]oxy]-2-(3-pvridyl)propylethanoic acid;

2-[[benzylhydroxyphosphinyl]oxy]-2-(tetrahydrofuranyl) methylethanoic acid;

2-[[benzylhydroxyphosphinyl]oxy]-2-(tetrahydrofuranyl) ethylethanoic acid;

2-[[benzylhydroxyphosphinyl]oxy]-2-(tetrahydrofuranyl) propylethanoic acid;

2-[[berizylhydroxyphosphinyl]oxy]-2-(2-indolyl)methylethanoic acid;

2-[[benzylhydroxyphosphinyl]oxy]-2-(3-indolyl) methylethanoic acid;

2-[[benzylhydroxyphosphinyl]oxy]-2-(4-indolyl) methylethanoic acid;

2-[[benzylhydroxyphosphinyl]oxy]-2-(3 -indolyl)ethylethanoic acid;

-382- [ [benzylhydroxyphosphinyl]oxy] -2- (3-indolyl)propylethanoic acid;

2- [ [benzylhydroxyphosphinyl] oxy] - 2- (2-thienyl) methylethanoic acid;

2- [ [benzylhydroxyphosphinyl] oxy] -2- (3-thienyl)methylethanoic acid ;

2- [[benzylhydroxyphosphinyl]oxy] -2- (4-thienyl)methylethanoic acid;

2- [ [benzylhydroxyphosphinyl] oxy] -2- (3-thienyl) ethylethanoic acid; and

2- [ (benzylhydroxyphosphinyl] oxy] -2- (3-thienyl)propvlethanoic acid.

In another preferred embodiment, R_x is a heterocyclic substituent illustrated by the compounds seiected from the group of formula III:

III wherein is Ar₃; and

R₂ is Cļ-C, straight or branched chain alkyl, C₂-C₉straight or branched chain alkenyl group, C₃-C_acycloalkyl, C_s-C₇ cycloalkenyl, or Ar., vvherein said alkyl, alkenyl, cycloalkyl, cycloalkenyl or aryl group may be optionally substituted vvith carboxylic

-39acid.

Especially preferred compounds vvherein R_x is.a heterocvclic group, R₂ is ethyl vvhich is substituted vvith carboxylic acid, and X is oxygen are selected from the group consisting of:

- [ [ (2-pyridyl)hydroxyphosphinyl] oxy] pentanedioic acid;

- [ [ (3-pyridyl) hydroxyphosphinvl] oxy] pentanedioic acid;

- [ [ (4-pyridyl) tiydroxyphosphinyl ] oxy] pentanedioic acid;

2- [ ((tetrahydrofuranyl) hydroxyphosphinyl] oxy] pentanedioic acid ;

- [ [ (2-indolyl) hydroxyphosphinyl] oxy] pentanedioic acid;

- [ [ (3 - indolyl) hydroxyphosphinyl] oxy] pentanedioic acid;

- [ [ (4-indolyl)hydroxyphosphinyljoxy] pentanedioic acid;

2-[[ <2-thienyl)hydroxyphosphinyl]oxy]pentanedioic acid;

2-[[ (3-thienyl) hydroxyphosphinyl ] oxy]pentanedioic acid; and 2 - [ [ (4 - thienyl) hydroxyphosphinyl ] oxy] pentanedioic acid.

Compounds of the present invention vvherein R_t is a 20 heterocvclic group, R₂ is phenyl, and X is oxygen are selected from the group consisting of:

2- [ [ (2-pyridyl)hydroxyphosphinyl] oxy] -2-p'nenylethanoic acid;

- [ [ (3-pyridyl) hydroxyphosphinyl] oxy] -2-phenylethanoic acid;

- [ [ (4-pyridyl) hydroxyphosphinyl] oxy] -2-phenylethanoic acid;

5 2 - [ [ (tecrahydrofuranyl) hydroxyphosphinyl] oxy] -2-phenylethanoic acid;

- [ [ (2 -indolyl) hydroxyphosphinyl] oxy] -2 -phenylethanoic acid;

2- [ [ (3 -indolyl) hydroxyphosphinyl] oxy] -2-phenylethanoic acid;

-402-([ (4-indolyl)hydroxyphosphinyl] oxy] -2-phenylethanoic acid; 2 - [ [ (2-thienyl)hydroxyphosphinyl] oxy] -2-phenylethanoic acid; 2-(((3-thienyl)hydroxyphosphinyljoxy] -2-phenylethanoic acid; and

- (((4-thienyl) hydroxyphosphinyl]oxy] -2-phenylethanoic acid.

Compounds are also preferably selected from the group of formula III:

O

Ri-P .

OH

Ra

COOH

III vvherein

R_l is hydrogen, Cj-Cj straight or branched chain alkyl, C₂-C₉ straight or branched chain alkenyl group, Cj-C_acycloalkyl, C_s-C₇ cycloalkenyl, or Ar_t; and

R, is Ar_t, vvherein said aryl group may be optionally substituted vvith carboxylic acid.

Particular species vvherein R_z is heterocyclic may be easilv made and used by persons of ordinary skill in the art in accordance vvith the teachings provided herein and knovvn in the art.

Compounds of the present invention vvherein R, is benzyl, R₂ is a heterocyclic group, and X is oxygen are selected from the group consisting of:

2- [ [benzylhydroxyphosphinyl] oxy] -2- (2-pvridyl) ethanoic acid;

-412- ( [benzylhydroxyphosphinyl] oxy] -2- (3-pyridyl)ethanoic acid;

2- [ [benzylhydroxyphosphinyl]oxy] -2- (4-pyridyl) ethanoic acid;

- [ [benzylhydroxyphosphinyl] oxy] -2- (tetrahydrofuranyl) ethanoic acid;

2-[ [benzylhydroxyphosphinyl] oxy]-2-(2-indolyl) ethanoic acid;

2-[[benzylhydroxyphosphinyl]oxy]-2-(3-indolyl)ethanoic acid;

2-[[benzylhydroxyphosphinyl]oxy]-2-(4-indolyl)ethanoic acid;

2-[[benzylhydroxyphosphinyl]oxy]-2-(2-thienyl)ethanoic acid;

2-[[benzylhydroxyphosphinyl]oxy]-2-{3-thienyl)ethanoic acid;

and

2-[[benzylhydroxyphosphinyl]oxy]-2-(4-thienyl)ethanoic acid.

Preferred phosphoramidate compounds are selected from formula IV:

R2

Ri15

OH 'N'

R1 'COOH

IV wherein

R.· is hydrogen, Ci-C, straight or branched chain alkyl, C₂-C₉ straight or branched chain alkenyl group, C₃-C₈cycloalkyl, C₅-C₇ cycloalkenyl, or Ar.; and

R₂ is Cļ-Cj straight or branched chain alkyl, C₂-C₉straight or branched chain alkenyl group, C₃-C₈ cycloalkyl, C_s-C₇ cycloalkenyl, or Ar_:, wherein said· alkyl, alkenyl, cycloalkyl, cycloalkenyl or aryl group may be optionally substituted with carboxylic

-42acid.

In a preferred embodiment, the R groups are straight branched aliphatic or carbocyclic substituents illustrated by the compounds selected from the group of formula IV:

Ri

OH p

COOH

IV wherein

Rļ is hydrogen, C_x-C₉ straight or branched chain alkyl, C₂-C₉ straight or branched chain alkenyl group, C₃-C₉cycloalkyl, C_s-C₇ cycloalkenyl, l-naphthyl, 2naphthyl, or phenyl; and

R₂ is Cļ-C₉ straight or branched chain alkyl, C₂-C₉straight or branched chain alkenyl group, C₃-C₈cycloalkyl, C_s-C₇ cycloalkenyl, l-naphthyl, 2naphthyl, or phenyl, wherein said alkyl, alkenyl, cycloalkyl, cycloalkenyl, l-naphthyl, 2-naphthyl, or pher.vl group may be optionally substituted with carboxylic acid.

Especiallv preferred compounds of Formula IV of the present invention wherein R_x is a straight or branched aliphatic group or a carbocyclic group, R₂ is ethyl which is substituted with a carboxylic acid, and the NR₃ is amino are selected from the group consisting of:

-432- [ [methylhydroxyphosphinyl]amino] pentanedioic acid;

2- [ [ethylhydroxyphosphinyl] amino] pentanedioic acid;

- [ [propylhydroxyphosphinyl] amino] pentanedioic acid;

- [ [butylhydroxyphosphinyl]amino] pentanedioic acid;

2-[ [cyclohexylhydroxyphosphinyl] 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- [ [phenyipropylhydroxyphosphinyl] amino]pentanedioic acid;

2- [ [phenylbutylhydroxyphosphinyl] amino] pentanedioic acid;

- [ [ (4-methylbenzyl) hydroxyphosphinyl] amino] pentanedioic acid; 2 - [ [ (4-fluorobenzyl) hydroxyphosphinyl] amino] pentanedioic acid;

2 -[[ (2-fluorobenzyl) hydroxyphosphinyl] amino] pentanedioic acid;

- [ [ (pentafluorobenzyl) hydroxyphosphinyl] amino] pentanedioic acid;

2- [ [ (methoxybenzyl) hydroxyphosphinyl] amino] pentanedioic acid; 2- [ [ (4 - fluoroohenyl) hydroxyphosphinyl] amino] pentanedioic acid;

2 - [ [ ( (hydroxy) phenylmethyl) hydroxyphosphinyl] amino] pentanedioic acid;

- [ [ (3-methylbenzyl) hydroxyphosphinyl] amino] pentanedioic acid; 2 -[(phosphono)amino]pentanedioic acid;

2- [((32 5 trif luoromethylbenzyl) hydroxyphosphinyl] amino] pentanedioic acid;

2-[[(2, 3, 4-trimethoxyphenyl) hydroxyphosphinyl] amino] pentanedioic acid;

-442-[[(l-naphthyl)hydroxyphosphinyl]amino]pentanedioic acid; 2-[[(2-naphthyl)hydroxyphosphinyl]amino]pentanedioic acid; 2-[[(l-naphthyl)methylhydroxyphosphinyl]amino]pentanedioic acid;

2-[[(2-naphthyl)methylhydroxyphosphinyl]amino]pentanedioic acid;

2- [[ (l-naphthyl)ethylhydroxyphosphinyl]amino]pentanedioic acid;

2-[[(2-naphthyl)ethylhydroxyphosphinyl]amino]pentanedioic acid;

2-[[(l-naphthyl)propylhydroxyphosphinyl]amino]pentanedioic acid;

2-[((2-naphthyl)propylhydroxyphosphinyl]amino]pentanedioic acid;

2-[[(l-naphthyl)butylhydroxyphosphinyl]amino]pentanedioic acid;

2-[[(2-naphthyl) butylhydroxyphosphinyl] amino] pentanedioic acid; and

2-[[ (phenylprop-2-enyl) hydroxyphosphinyl] amino] pentanedioic acid.

Especially preferred compounds of Formula IV of the present invention vvherein R_x is a straight or branched aliphatic group or a carbocyclic group, R₂ is ethyl vvhich is substituted vvith a carboxylic acid, and the NR_X is amino are selected from the group consisting of:

2-((benzylhydroxyphosphinyl)amino]pentanedioic acid;

2- [ (phenylhydroxyphosphinyl)amino]pentanedioic acid;

-452- [ [ ( (hydroxy) phenylmethyl) hydroxyphosphinyl] amino] pentanedioic acid;

2- [ (butylhydroxyphosphinyl) amino] pentanedioic acid;

- [ [ (3-methylbenzyl) hydroxyphosphinyl] amino] pentanedioic acid; 2 - [ (3 -phenylpropylhydroxyphosphinyl) amino] pentanedioic acid;

2- [ [ (4-fluorophenyl) hydroxyphosphinyl] amino] pentanedioic acid; 2 - [ (methylhydroxyphosphinyl) amino] pentanedioic acid;

2- [ (phenylethylhydroxyphosphinyl) amino] pentanedioic acid;

- ( [ (4-methylbenzyl) hydroxyphosphinyl] amino] pentanedioic acid; 2 - [ [ (4 -fluorobenzyl) hydroxyphosphinyl] amino] pentanedioic acid; 2- [ [ (4-methoxybenzyl) hydroxyphosphinyl] amino] pentanedioic acid;

- [ [ (2-fluorobenzyl) hydroxyphosphinyl] amino] pentanedioic acid; 2 - [ C (pentaf luorobenzyl) hydroxyphosphinyl] amino] pentanedioic acid;

2-[(phosphono)amino]pentanedioic acid; and

2-[ l (3trif luoromethylbenzyl) hydroxyphosphinyl] amino] pentanedioic acid.

Compounds of the present invention vvherein R_x is a straight or branched aliphatic group or a carbocyclic group, R₂is phenyl, and X is amino are selected from the group consisting of:

2- [ [methylhydroxyphosphinyl] amino] -2-phenylethanoic acid;

2- [ [ethylhydroxyphcsphinyl ] amino] -2-phenylethanoic acid;

2- [ (propylhydroxyphosphinyl] amino] -2-phenylethanoic acid;

2- [ [butylhydroxyphosphinyl] amino] -2-phenylethanoic acid;

-462- [ [cyclohexylhydroxyphosphinyl] amino] -2-phenylethanoic acid;

- [ [ (cyclohexyl) methylhydroxyphosphinyl] amino] -2-phenyl ethanoic acid;

2-[[phenylhydroxyphosphinyl]amino]-2-phenylethanoic acid;

2-[[benzylhydroxyphosphinyl]amino]-2-phenylethanoic acid;

2-[[phenylethylhydroxyphosphinyl]amino]-2-phenylethanoic acid; 2-[[phenylpropyihydroxyphosphinyl]amino]-2-phenylethanoic acid;

2-[[phenylbutyihydroxyphosphinyl]amino]-2-phenylethanoic acid; 10 2-EE(2, 3, 4-trimethoxyphenyl)-3-hydroxyphosphinyl]amino]-2phenylethanoic acid;

- [[(l-naphthyl)hydroxyphosphinyl]aminoj-2-phenylethanoic acid;

2-[[(2-naphthyl)hydroxyphosphinyl]amino]-2-phenylethanoic 15 acid;

2-[[(l-naphthyl)methylhydroxyphosphinyl)]amino]-2-phenyl ethanoic acid;

2-[E(2-naphthyi)methylhydroxyphosphinyl]amino]-2-phenyl ethanoic acid;

2-[t(l-naphthyi)ethylhydroxyphosphinyl]amino]-2-phenylethanoic acid;

2-[[(2-naphthyl)ethylhydroxyphosphinyl]amino]-2-phenylethanoic acid;

2-[[(l-naphthyl)propylhydroxyphosphinyl]amino]-2-phenyl 25 ethanoic acid;

2-([(2-naphthyl}propylhydroxyphosphinyl]amino]-2-phenyl ethanoic acid;

2-EE(l-naphthyl)butylhydroxyphosphinyl]amino]-2-pnenylethanoic

-47acid;

2- [ [ (2-naphthyl) butylhydroxyphosphinyl] amino] -2-phenylethanoic acid; and

2- [ [phenylprop-2-enylhydroxyphosphinyl] amino] -2-phenylethanoic acid.

Although not limited to any one particular species, a highly preferred phosphoramidate species vvhere R_x is aliphatic or carbocyclic, R, is ethyl vvhich is substituted vvith carboxylic acid, and X is amino is

2- [ [benzylhydroxyphosphinyl] amino]pentanedioic acid.

Other especially preferred compounds are selected from the group consisting of:

phosphoramidate derivatives vvherein X is amino, R_x is a straight or branched aliphatic group or a carbocyclic group, and R₂ is an C₂-C_e alkyl or alkenyl chain vvhich is substituted vvith a carboxylic acid. Exemplary Species include:

-[(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] nonanedioic acid;

2- [ (benzylhydroxyphosphinyl) amino] nonanedioic acid;

2-[ (methylhydroxyphosphinyl) amino] decanedioic acid; and 2- [ (benzylh.ydroxyphosph.inyl) amino] decanedioic acid.

-48Other especially preferred compounds are selected from the group consisting of:

phosphoramidate derivatives wherein X is amino, R. is benzyl, and Rj is a straight or branched aliphatic group or a carbocyclic group. Exemplary species include:

2- [ [benzylhydroxyphosphinyl] amino] -2-methylethanoic acid;

2-[[benzylhydroxyphosphinyl]amino]-2-ethylethanoic acid;

2-[[benzylhydroxyphosphinyl]amino]-2-propylethanoic acid;

2-([benzylhydroxyphosphinyl]amino]-2-butylethanoic acid;

2-[[benzylhydroxyphosphinyl]amino]-2-cyclohexylethanoic acid; 2-[[benzylhydroxyphosphinyl]amino]-2-(cyclohexyl)methyl ethanoic acid;

2-[[benzylhydroxyphosphinyl]amino]-2-phenylethanoic acid;

2-[[benzylhydroxyphosphinyl]amino]-2-benzylethanoic acid;

2-[[benzylhydroxyphosphinyl]amino]-2-phenylethylethanoic acid; 2-[[benzylhydroxyphosphinyl]amino]-2-phenylpropylethanoic acid;

2-[[benzylhydroxyphosphinyl]amino]-2-phenylbutylethanoic acid; 2-[[benzylhydroxyphosphinyl]amino]-2-(2 , 3, 4trimethoxyphenyl)ethanoic acid;

2-[[benzylhydroxyphosphinyl]amino]-2-(l-naphthyl)ethanoic acid;

2- [ [benzylhydroxyphosphinyl] amino] -2- (2-naphthyl) ethanoic acid;

2- ([benzylhydroxyphosphinyl] amino] - 2- (l-naphthyl) methyl ethanoic acid;

2- [ [benzylhydroxyphosphinyl] amino] -2- (2-naphthyl) methyl ethanoic acid;

-492- [ [benzylhydroxyphosphinyl] amino] -2- (l-naphthyl) ethylethanoic acid;

2- [ [benzylhydroxyphosphinyl] amino] -2- (2-naphthyl)ethylethanoic acid;

2- [ [benzylhydroxyphosphinyl] amino] -2- (l-naphthyl) propyl ethanoic acid;

2-[[benzylhydroxyphosphinyl] amino]-2-(2-naphthyl)propyl ethanoic acid;

2-[[benzylhydroxyphosphinyl]amino]-2-(1-naphthyl)butylethanoic acid ;

2-[[benzylhydroxyphosphinyl] amino]-2-(2-naphthyl)butylethanoic acid; and

2-([benzylhydroxyphosphinyl]amino]-2-phenylprop-2-enylethanoic acid.

Especially preferred methods utilizē compounds vvherein R_xis said alkyl, alkenyl, cycloalkyl, or aryl group vvhich is substituted vvith a heterocyclic group, R₂ is ethyl vvhich is substituted vvith carboxylic acid, and X is amino are selected from the group consisting of:

2- [ [ (2-pyridyl) methylhydroxyphosphinyl] amino] pentanedioic acid;

2-([(3-pyridyl)methylhydroxyphosphinyl]amino]pentanedioic acid;

2-[[<4-pyridyl)methylhydroxyphosphinyl]amino]pentanedioic acid;

2- ( [ (3-pyridyl) eth.ylhydroxyphosph.inyl] amino] pentanedioic acid;

2-[[(3-pyridyl)propylhydroxyphosphinyl]amino]pentanedioic

-50acid;

- [ [ (tetrahydrofuranyl) methylhydroxyphosphinyl] amino] pentanedioic acid;

2- [ [ (tetrahydrofuranyl) ethylhydroxyphosphinyl] amino] pentanedioic acid;

2- [ [ (tetrahydrofuranyl)propylhydroxyphosphinyl] amino] pentanedioic acid;

- [ [ (2-indolyl) methylhydroxyphosphinyl] amino]pentanedioic acid;

2 - [ [ (3-indolyl) methylhydroxyphosphinyl] amino] pentanedioic acid;

- [ [ (4-indolyl) methylhydroxyphosphinyl] amino] pentanedioic acid;

- [ [ (3-indolyl) ethylhydroxyphosphinyl] amino]pentanedioic acid; 15 2- [ [ (3-indolyl)propylhydroxyphosphinyl] amino] pentanedioic acid;

- [ [ (2-thienyl)methylhydroxyphosphinyl] amino] pentanedioic acid;

- [ [ (3-thienyl)methylhydroxyphosphinyl] amino] pentanedioic 20 acid;

2- [ [ (4-thienyl)methylhydroxyphosphinyl] amino] pentanedioic acid;

- [ [ (3-thienyl) ethylhydroxyphosphinyl] amino] pentanedioic acid; and

5 2 - [ [ (3 - thienyl) propylhydroxyphosphinyl] amino] pentanedioic acid.

Especially preferred methods utilizē compounds wherein R_x

-51is said alkyl, alkenyl, cycloalkyl, or aryl group vvhich is substituted with a heterocyclic group, R₂ is phenyl, and X is amino are seiected from the group consisting of:

2- [ [ (2-pyridyl)methylhydroxyphosphinyl] amino] -2-phenylethanoic acid;

2- [ [ (3-pyridyl) methylhydroxyphosphinyl] amino] -2-phenylethanoic acid;

2- C [ (4-pyriayl) methylhydroxyphosphinyl] amino] -2-phenylethanoic acid;

2- [ [ (3-pyridyl)ethylhydroxyphosphinyl]amino]-2-phenylethanoic acid;

- [ [ (3-pyridyl) propylhydroxyphosphinyl] amino] -2-phenylethanoic acid;

2- [ [ (tetrahydrofuranyl)methylhydroxyphosphinyl]amino]-2-phenyl ethanoic acid;

- [ [ (tetrahydrofuranyl)ethylhydroxyphosphinyl]amino]-2-phenyl ethanoic acid;

2- [ [ (tetrahydrofuranyl) propylhydroxyphosphinyl] amino]-2-phenyl ethanoic acid;

2- [ [ (2-in.dolyl)methylhydroxyphosphinyl] amino] -2-phenylethanoic acid;

2-[ [ (3-indolyl) methylhydroxyphosphinyl] amino]-2-phenylethanoic acid;

2- [ [ (4-indolyl)methylhydroxyphosphinyl] amino]-2-phenylethanoic acid;

2- [ [ (3-indclyl)ethylhyaroxyphosphinyl]amino]-2-phenylethanoio acid;

- [ [ (3 -indolyl)propylhydroxyphosphinyl]amino]-2-phenylethanoic

-52acid;

- ( [ (2-thienyl) methylhydroxyphosphinyl] amino] -2-phenylethanoic acid;

2- [ [ (3-thienyl) methylhydroxyphosphinyl] amino] -2-phenylethanoic acid;

- [ [ (4-thienyl) methylhydroxyphosphinyl] amino] -2-phenylethanoic acid;

2- [ [ (3-thienyl) ethylhydroxyphosphinyl] amino] -2-phenylethanoic acid; and

2- [ [ (3-thienyl)propylhydroxyphosphinyl] amino] -2-phenylethanoic acid.

Especially preferred methods utilizē compounds vvherein R_xis benzyl, R₂ is said alkyl, alkenyl, cycloalkyl, or aryl group vvhich is substituted vvith a heterocyclic group, and X is amino are selected from the group consisting of:

2- I [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;

-532-[[benzylhydroxyphosphinyl]amino]-2-(tetrahydrofuranyl)ethyl ethanoic acid;

2-[[benzylhydroxyphosphinyl]amino]-2-(tetrahydrofuranyl) propylethanoic acid;

2-[[benzylhydroxyphosphinyl]amino]-2-(2-indolyl)methylethanoic acid;

2-[[benzylhydroxypnosphinyl]amino]-2-(3-indolyl)methylethanoic acid;

2-[[benzylhydroxyphosphinyl]amino]-2-(4-indolyl)methylethanoic acid;

2-[(benzylnydroxyphosphinyl]amino]-2-(3 -indolyl)ethylethanoic acid;

2-[[benzylhydroxyphosphinyl]amino]-2-(3-indolyl)propylethanoic acid;

2-[[benzylhydroxyņhosphinyl]amino]-2-(2-thienyl)methylethanoic acid;

2-[[benzylhydroxyphosphinyl]amino]-2-(3-thienyl)methvlethanoic acid;

2-[[benzylhydroxyphosphinyl]amino]-2-(4-thienyl)methylethanoic acid;

2-[[berizylhydroxyphosphinyl]amino]-2-(3-thienyl) ethylethanoic acid; and

2-([benzylhydroxyphosphinyl]amino]-2-(3-thienyl)propylethanoic acid.

In another preferred embodiment, R_L is a heterocyclic substituent illustrated by the compounds selected from the group of formula IV:

-54R2

RiOH 'N'

R1 'COOH

IV wherein

Rļ is Ar_x; and

R₂ is Οχ-Ο, straight or branched chain alkyl, C₂-C, straight or branched chain alkenyl group, C₃-C_acycloalkyl_i C₅-C, cycloalkenyl, or Ar., v/herein said alkyl, alkenyl, cycloalkyl, cvcloalkenyl or aryl group may be optionally substituted vith carbcxylic acid.

Especially preferred compounds wherein R_x is a heterocyclic group, R₂ is ethyl which is substituted with carboxylic acid, and X is amino are selected from the group consisting of:

2-[[(2-pyridyl)hydroxyphosphinyl]amino]pentanedioic acid;

2-C C(3-pyridyl)hydroxyphosphinyl]amino]pentanedioic acid;

2-[[<4-pyridyl)hydroxyphosphinyl]amino]pentanedioic acid;

- £[{tetrahydrofuranyl)hydroxyphosphinyl]amino]pentanedioic acid;

2-([(2-indolyl)hydroxyphosphinyl]amino]pentanedioic acid;

-[[{3-indolyl)hydroxyphosphinyl]amino]pentanedioic acid;

2-[[{4-indolyl)hydroxyphosphinyl]amino]pentanedioic acid;

2-[[(2 -thienyl)hydroxyphosphinyl]amino]pentanedioic acid;

2-[[(3-thienyl)hydroxyphosphinyl]amino]pentanedioic acid; and

-552 - [ [ (4-thienyl)hydroxyphosphinyl] amino] pentanedioic acid.

Compounds of the present invention wherein Rļ is a heterocyclic group, R₂ is phenyl, and X is amino are selected from the group consisting of:

- [ [ (2-pyridyl) hydroxyphosphinyl] amino] -2-phenylethanoic acid; 2 - [ [ (3-pyridyl)hydroxyphosphinyl]amino] -2-phenylethanoic acid; 2- [ [ (4-pyridyl) hydroxyphosphinyl] amino] -2-phenylethanoic acid; 2-[[(tetrahydrofuranyl)hydroxyphosphinyl] amino] -2-phenyl ethanoic acid;

2-([(2-indolyl)hydroxyphosphinyl]amino]-2-phenylethanoic acid; 2 - [ [ (3 -indolyl) hydroxyphosphinyl] amino] -2-phenylethanoic acid; 2- [ [ (4-indolyl) hydroxyphosphinyl] amino] -2-phenylethanoic acid; 2- [ [ (2-thienyl) hydroxyphosphinyl] amino] -2-phenylethanoic acid; 2- [ ((3 - thienyl) hydroxyphosphinyl] amino] -2-phenylethanoic acid; and

2- [ ((4-thienyl)hydroxyphosphinyl]amino) -2-phenylethanoic acid.

Compounds are also preferably selected from the group of formula IV:

OH

IV wherein

R, is hydrogen, Cļ-C, straight or branched chain alkyl, C₂-C, straight or branched chain alkenyl group, C₃-C₉

-56cycloalkyl, C_s-C₇ cycloalkenyl, or Ar_lz· and

Rj is Ar_lz v/herein said aryl group may be optionally substituted vvith carboxylic acid.

Compounds of the present invention vvherein R_x is benzyl, R₂ is heterocyclic, and X is amino are selected from the group consisting of:

2-[ [benzylhydroxyphosphinyl]amino]-2-(2-pyridyl)ethanoic acid; 2-[[benzylhydroxyphosphinyl]amino]-2-{3-pyridyl)ethanoic acid; 2-[[benzylhydroxyphosphinyl]amino]-2-(4-pyridyl)ethanoic acid; 2-[[benzylhydroxyphosphinyl]amino]-2-(tetrahydrofuranyl) ethanoic acid;

2-[[benzylhydroxyphosphinyl]amino]-2-(2-indolyl)ethanoic acid; 2-[[benzylhydroxyphosphinyl]amino]-2-(3-indolyl)ethanoic acid;

I

2- [ [benzylhydroxyphosphinyl]amino]-2-(4-indolyl)ethanoic acid; 2-[[benzylhydroxyphosphinyl]amino]-2-(2-thienyl)ethanoic acid; 2- [ [benzylhydroxyphosphinyl]amino]-2-(3-thienyl)ethanoic acid; and

2-[[benzylhydroxyphosphinyl]amino]-2-(4-thienyl)ethanoic acid.

Svnthesis of Compounds

The compounds of the present invention can be readily prepared by Standard techniques of organic chemistry, utilizing the general synthetic pathways depicted belovv (see

-57Schemes Ι-ΙΧ). Precursor compounds may be prepared by methods knovvn in the art, such as those described in the method of Jackson et al. (J. Med. Chem. 39(2), 619-622, Desion,

Svnthesis, and Biological Activitv of a Potent Inhibitor of the Neuropeptidase N-Acetvlated a-Linked Acidic Dipeptidase) and, for example, in Froestl et al. (J. Med. Chem., 1995, 38,

3313-3331, Phosphinic Acid Analogues of GABA) .

SCHEME I

HO

Production of compounds containing the R group substitutions can be easily made utilizing knovvn methods. Further methods of synthesizing phosphinic acid esters are also described in J. Med. Chem., 1988, 31, 204-212, and may be found in Scheme II, belovv.

-58SCHEME II

Method A

NaHzPCU R-CH-=.CEL· -*AIBN

H2SO4

EtOH

R-(CHz)2

OH

-H

O

R'-P-H

				OH
5	A.	R'= (CH₂)₃Ph	H.	n-C₇H_u
	B.	(CH, )₄Ph	I .	n-C_sK,₇
	C.	(CH₂) ₅Ph	J.	n-C,H?₃
	D.	(CH₂)₄ (P-F-Ph)	K.	n- C₁₀H₂₁
	E.	(CH₂)₄- (3-pyridyl)	L.	CH, (CH) (CHj) C₄H,
10	F.	n-C_sH,,	M.	CH,(CH₃)CH(CH₃)₂
	G.	n-C_sH

Method B

Cl-P(OEt> 1. KO’

R'-MgX -► R'-P(OEt> -»

2. aq.NaOH

R'-H

OH

N. R'= n-C₄H_s

O. CHCCHJCsH,.,.

Starting with the aforementioned phosphinic acid esters, there are a varietv of routes that can be used to prepare the compounds of the present invention. For example, a general route was recently described in J. Med. Chem., 1956, 39, 619LV 12253

-59622, and is set forth belovv in Scheme III.

COOBn '_p_ l.TMSOJ^N

ROH

H2 Pd/C 'COOBn

OH ;OOBn

SCHEME ΙΠ

Another route for preparing the compounds of the present invention is as set forth belovv in scheme IV and Scheme V. Scheme IV and Scheme V also shovv a phosphinic acid derivative as a starting material to prepare the compounds of the present invention and the R group is contemplated as including anv reasonable Chemical substitution and includes vvithout limitation che R groups listed in Scheme II and vvithin the specification.

-60RORi

-H

1. TMSCI, EfcN

R'CChBn

2.

CChBn

'CChBn

Ha, Pd/C HaO

ORi

SCHEME IV o

H-p-H + RBr

O-NH4+

i) HMDS ļf ii) HCI ļ|

->- R-p-_H iii) BnOH, EDC ;

OBn

SCHEME V

-61Another route of preparing the compounds of the present invention allovvs for aromatic substitution at Rl and is set forth belovv in Scheme VI.

O

SCHEME VI

Another route of preparing the compounds of the present invention allovvs fcr aromatic substitution at the R2 position and is set forth belovv in Scheme VII.

-62EtO

NaOEt R-Br *

HCHO

EfcNH (R’Bn)

(Bn)(BnO)P(O)H

Bu»NHSO»

KāCLb *

▼

SCHEME VII

-63Preparation of the vvherein X is NR1 is set compounds of the present invention forth belovv in Scheme VIII.

SCHEME VIII

-64Preparation of the compounds of the present vvherein X is οχνσεη is set forth belovv in Scheme invention

IX.

R-P-K i

ļ

HO

H2, Pd/C, HO

I. DCC, DMAP, THF

2. NaICU

SCHEME IX

Pharmaceutical Compositions of the Present Invention

The present invention also relates to a pharmaceutical composition comprising:

(i) a therapeutically effective amount of a compound of formulas I, II, III or IV; and (ii) a pharmaceutically acceptable carrier.

In another preferred embodiment, the pharmaceutical composition further comprises a therapeutic aģent selected frcm the group consisting of therapeutic hormones, chemotherapeutic aģents, monoclonal antibodies, antianciogenesis aģents, radiolabelied compounds, antineoplastic

-65agents and mixtures thereof. Examples of therapeutio hormones include diethylstilbestrcl (DES), leuprolide, flutamide, cyproterone acetate, ketoconazole and amino glutethimide are preferred. Examples of antineoplastic aģents include 5fluorouracil, vinblastine sulfate, estramustine phosphate, suramin and strontium-89. Examples of chemotherapeutic aģents include buserelin, chlorotranisene, chromic phosphate, cisplatin, cyclophosphamide, dexamethasone, doxorubicin, estradiol, estradiol valerate, estrogens conjugated and eszerified, estrone, ethinyl estradiol, floxuridine, goserelin, hydroxyurea, melphalan, methotrexate, mitomycin and prednisone.

In a further preferred embodiment, the compound of formula I, ΣΙ, III or IV is present in an amount that is effective for inhibiting NAALADase activity in an animal or treating a prostate disease in an animal.

Process for Prenarino Pharmaceutical Compositions

In yet another preferred embodiment, a process for preparing a pharmaceutical composition or medicament containing a compound of the present invention for treating a disease is also contemplated.

Methods of Use of the Present Invention

i) Method of inhibitinc NAALADase enzvme activitv

The present invention further reiates to a method of inhibiting NAALADase enzyme activicy in an animal, comprising

-66administering an effective amount of a compound of formula I,

II, III or IV to said animal.

ii? Method of treating a prostate disease

The present invention also relates to a method of treating a prostate disease in an animal, comprising administering an effective amount of a compound of formula I, II, III or IV to said animal.

In a preferred embodiment, said prostate disease is prostate cancer such as prostatic adenocarcinoma, benign prostatic hyperplasia, or conditions involving the prostate requiring administration of the compounds of the present invention, such prostatic intraepithelial neoplasia (PIN).

iii) Method of treatino cancer

In addition tc prostate cancer, other forms of cancer that may be treated vvith the compounds cf the present invention include vvithout limitation: ACTH-producing tumors, acute lymphocytic leukemia, acute nonlympnocytic leukemia, cancer of the adrenal cortex, bladder cancer, brain cancer, breast cancer, cervix cancer, chronic lymphocytic leukemia, chronic myelocytic leukemia, colorectal cancer, cutaneous Tcell lymphoma, endometrial cancer, esophageal cancer, Evving's sarcoma, gallbladder cancer, hairy celi leukemia, head & neck cancer, Hodgkin's lymphoma, Kaposi's sarcoma, kidney cancer, liver cancer, lung cancer(small and/or non-small celi), malignant periconeai effusion, malignant pleural effusion, melanoma, mesothelioma, multiple myeloma, neuroblastoma, nonLV 12253

-67Hodgkin's lymphoma, osteosarcoma, ovary cancer, ovarv (germ celi) cancer, pancreatic cancer, penis cancer, retinoblastoma, skin cancer, soft-tissue sarcoma, sguamous celi carcinomas, stomach cancer, testicular cancer, thyroid cancer, trophoblastic neoplasms, cancer of the uterus, vaginai cancer, cancer of the vulva and Wilm's tumor.

The compounds of the present invention are particularly useful in treating cancer of tissues where NAALADase enzymes reside. Such tissues include the prostate as well as the brain, kidney and testis.

For patients who initially present without advanced or metastatic cancer, NAALADase inhibitor based drugs are used as an immediate initial therapy prior to surgery and radiation therapy, and as a continuous post-treatment therapy in patients at risk for recurrence or metastasis (based upon high PSA, high Gleascn's score, locallv extensive disease, and/or pathological evidence of tumor invasion in the surgical specimen). The goal in these patients is to inhibit the growth of potentially metastatic celis from the primary tumor during surgery or radiotherapy and inhibit the growth of tumor celis from undetectable residual primary tumor.

For pacients who initially present with advanced or metastatic cancer, NAALADase inhibitor based drugs are used as a continuous supplement to, or possible as a replacement for hormonal ablation. The goal in these patients is to slow ⁴tumor celi growth from both the untreated primary tumor and from the existing metastatic lesions.

In addition, the invention may be particularly

-68efficacious during post-surgical recovery, vvhere the present compositions and methods may be particularly effective in lessening the chances of recurrence of a tumor engendered by shed celis that cannot be removed by surgical intervention.

iv) Diagnostic kits

The present invention also includes a diagnostic kit for performing the methods of the present invention and may contain compounds and/or compositions containing the compounds of the present invention. Radiolabelled compounds and monocional antibodies may be used in a manner so as to provide diagnostic information. Examples of diagnostic information and uses include determining the type of disease, the progress of the particular disease, the location of celis targeted by a NAALADase inhibitor, radiolabelled compound or monocional antibody, and similar diagnostic uses knovvn to persons skilled in the art.

Route of Administration

In the methods of the present invention, the compounds may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally or via an implanted reservoir in dosage formulations containing conventional non-toxic pharmaceutically-acceptable carriers, adjuvants and vehicles. The term parenteral as used herein includes subcutaneous, intravenous, intramuscular, intraperitoneal, intrathecal, intraventricular, intrasternal or intracranial injection and infusion technigues. Invasive

-69techniques are preferred, particularly direct administration to damaged neuronal tissue.

To be effective therapeutically as Central nervous system targets, the compounds of the present invention should readily penetrate the blood-brain barrier vvhen peripherally administered. Compounds vvhich cannot penetrate the bloodbrain 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 agueous or oleaginous suspensions. These suspensions can be formulated according to technioues knovvn in the art using suitable dispersing or vvetcing aģents and suspending aģents. The sterile injectable preparations may also be sterile injectable Solutions or suspensions in nontoxic parenterally-acceptable diluents or solvents, for example, as Solutions in 1,3-butanediol. Among the acceptable vehicles and solvents that may be emploved are vvater, Ringer's solution and isotonic sodium chloride solution. In addition, sterile fixed oils are conventionally emploved as solvents or suspending mediums. For this purpose, any bland fixed oil such as a synthetic mono- or di-glyceride may be employed. Fatty acids such as oleic acid and its glyceride derivatives, including olive oil and castor oil, especially in their polyoxyethylated forms, are useful in the preparation of injectables. These oil Solutions or suspensions may also concain long-chain alcohol diluents or dispersants.

Additionally, the compounds may be administered orally in

-70the form of capsules, tablets, aqueous suspensions or

Solutions. Tablets may contain carriers such as lactose and corn starch, and/or lubricating aģents such as magnesium stearate. Capsules may contain diluents ineluding lactose and dried corn starch. Aqueous suspensions may contain emulsifying and suspending aģents combined with the active ingredient. The oral dosage forms may further contain sweetening and/or flavoring and/or coloring aģents.

The compounds may further be administered rectally in the form of suppositories. These compositions can be prepared by mixing the drug with suitable non-irritating excipients which are solid at room temperature, but liquid at rectal temperature such that they will melt in the rectum to release the drug. Such excipients include cocoa butter, beeswax and polyethylene glycols.

Moreover, the compounds may be administered topically, especiallv when the conditions addressed for treatment involve areas or orgāns readily accessible bv topical application, ineluding neurological disorders of the eye, the skin or the lower intestinal tract.

For topical application to the eye, or ophthalmic use, the compounds can be formulated as micronized suspensions in isotonic, pH adjusted sterile saline or, preferably, as a solution in isotonic, pH adjusted sterile saline, either with or vithout a preservative such as benzylalkonium chloride. Alternativelv, the compounds may be formulated into oinements, such as petrolatum.

For topical application to the skin, the compounds can be

-71formulated into suitable ointments containing the compounds suspended or dissolved in, for example, mixtures with one or more of the foliowing: mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene polyoxypropylene compound, emulsifying wax and water. Alternatively, the compounds can be formulated into suitable lotions or creams containing the active compound suspended or dissolved in, for example, a mixture of one or more of the following: mineral oil, sorbitan monostearate, polysorbate 60, cetyl ester wax, cetearvl alcohol, 2-octyldodecanol, benzyl alcohol and water.

Topical application to the lower intestinal tract can be effected in rectal suppository formulations (see above) or in suitable enema formulations.

The compounds of the present invention may be administered by a single dose, multiple discrete doses or continuous infusion. Since the compounds are small, easily diffusible and relatively stable, they are well suited to continuous infusion. Pump means, particularly subcutaneous pump means, are preferred for continuous infusion.

Compositions and methods of the invention also may utilizē controlled release technology. Thus, for example, NAALADase inhibitors may be incorporated into a polymer matrix for controlled release over a period of days. Such controlled release films are well known to the art. Examples of polymers commonly employed for this purpose thac may be used in the present invention include nondegradable ethylene-vinyl acetate copolymer and degradable lactic acid-glvcolic acid copolymers. Certain hydrogels such as poly(hydroxyethylmethacrylate) or

-72poly(vinylalcohol) also may be useful.

Dosaoe

Dose Ievels on the order of about 0.1 mg to about 10,000 mg cf the active ingredient compound are useful in the treatment of the above conditions, vvith preferred Ievels being about 0.1 mg to about 1,000 mg. The specific dose Ievel for any particular patient vvill vary depending upon a variety of factors, including the activitv of the specific compound employed; the age, body vveight, general health, sex and diet of the patient; the time of administration; the rāte of excretion; drug combination; the severi'ty of the particular disease being treated; and the form of administration. Typically, in vitro dosage-effect results provide useful guidance on the proper doses for patient administration. Studies in anirnal models are also helpful, particularly in determining effective doses for treating cancer. The considerations for determining the proper dose Ievels are vvell knovvn in the art.

In a preferred embodiment, the compounds of the present invention are administered in lyophilized form. In this case, ce 100 mg of a compound of the present invention may be lyophilized in individual vials, together vvith a carrier and a buffer, such as mannitol and sodium phosphate. The compound may be reconstituted in the vials vvith bacteriostatic vvater before administration.

As previouslv mentioned, the compounds of the present invention may be administered in combination vvith one or more

-73therapeutic aģents, including chemotherapeutic aģents. TABLE I provides knovvn median dosages for selected chemotherapeutic aģents. Specific dose Ievels for these aģents will depend upon considerations such as those identified above for the compounds of the present invention.

-74TABLE I

CHEMOTHERAPEUTIC AĢENT	MEDIAN DOSAGE
Asparaginase	10,000 units
Bleomycin Sulfate	15 units
Carboplatin	50-450 mg
Carmustine	100 mg
Cisplatin	10-50 mg
Cladribine	10 mg
Cvclophosphamide (Ivophilized)	100 mg-2 gm
Cyclophosphamide (nonlvophilized)	100 mg- 2 gm
Cyoarabine (lyophilized povvder)	100 mg-2 gm
Dacarbazine	100 mg-200 mg
Dactinomvcin	0.5 mg
Daunorubicin	2 0 mg
Diethylstilbestrol	250 mg
Doxorubicin	10-150 mg
Etidronate	3 00 mg
Etoposide	10 0 mg
Fioxuridine	50 0 mg
Fludarabine Phosphate	5 0 mg
Fluorouracil	500 mg-5 gm
Goserelin	3 . 6 mg
Granisetron Hydrochloride	1 mg
Idarubicin	5-10 mg
Ifosfamide	1-3 gm
Leucovorin Calcium	50-350 mg
Leuprolide	3.75-7.5 mg
Mechloretnamine	10 mg
Medroxyprcgescerone	1 gm
Melphalan	50 gm
Methotrexate	20 mg-1 gm

CHEMOTHERAPEUTIC AĢENT	MEDIAN DOSAGE
Mitomycin	5-40 mg
Mitoxantrone	20-30 mg
Ondansetron Hvdrochloride	40 mg
Paclitaxel	3 0 mg
Pamidronate Disodium	30-*90 mg
Pegaspargase	750 units
?licamycin	2,500 mcgm
Streptozocin	1 gm
Thiotepa	15 mg
Teniposide	5 0 mg
Vinblastine	10 mg
Vincristine	1-5 mg
Aldesleukin	22 million units
Epoetin Alpha	2,000-10,000 units
Filgrastim	300-480 mcgm
Immune Globulin	500 mg-10 gm
Interferon Alpha-2a	3-36 million units
Interferon Alpha-2b	3-50 million units
Levamisole	50 mg
Octreotide	1,000-5,000 mcgm
Sargramostim	250-500 mcgm

Administration reoimen

For the methods of the present invention, any administration rsgimen regulating the timing and secuence of drug deiivery can be used and repeated as necessary to effect treatment. Such regimen mav include pretreatment and/or coadministration with additional therapeutic aģents.

-76For patients vvith prostate cancer that is neither advanced nor metastatic, the compounds of the present invention may be administered (i) prior to surgery or radiation treatment to reduce the risk of metastasis; (ii) during surgery or.in conjunction vvith radiation treatment; and/or (iii) after surgery or radiation therapy to reduce the risk of recurrence and to inhibit the grovvth of any residual cumorous celis.

For patients vvith advanced or metastatic prostate cancer, the compounds of the present invention may be administered as a continuous supplement to, or as a replacement for, hormonal ablation in order to slovv tumor celi grovvth in both the ur.treated primary tumor and the existing metastatic lesions.

The methods of the present invention are particularly useful vvhere shed celis could not be removed by surgical interver.tion. After post-surgical recovery, the methods of the present invention vvould be effective in reducing the chances of recurrence of a tumor engendered by such shed celis.

Combination vvith Other Treatments (i) Surcerv and Radiation Treatment

In general, surgery and radiation treatment are employed as poter.cially curative therapies for patients vvith localized prostate cancer vvho are under 70 years or age and are expected to live at least 10 more years.

Approximately 70% of newly diagnosed prostate cancer pacients fall into this categorv. Approximately 90% of these

-77patients (65% of total patients) undergo surgery, vvhile approximately 10% of these patients (7% of total patients) undergo radiation treatment.

Histopathological examination of surgical specimens reveals that approximately 63% of patients undergoing surgery (40% of total patients) have locally extensive tumors or regional (lymph node) metastasis that was undetected at initial diagnosis. These patients are at a significantly greater risk of recurrence. Approximately 40% of these patients vvill actually develop recurrence vvithin five years after surgery. Results after radiation treatment are even less encouraging. Approximately 80% of patients who have undergone radiation treatment as their primary therapy have disease persistence or develop recurrence or metastasis vvithin five years after treatment.

Currently, most prostate cancer pacients undergoing surgery and radiation treatment do not receive any immediate follow-up therapy. Rather, they are monitored frequently for elevated Prostate Specific Antigen (PSA), vvhich is the primary indicator of recurrence or metastasis.

Based on the above statistics, there is considerable opportunity to use the present invention in conjunction vvith surgery and/or radiation treatment.

(ii) Hormonal Therapv

Hormonal ablation is the most effective palliative treatment for the 10% of patients vvith metastatic prostate cancer. Hormonal ablation by medication and/or orchiectomy is used to block hormones that promote further grovvth and

-78metastasis of prostate cancer. With time, both the primary and metastatic tumors of virtually ali of these patients become hormone-independent and resistant to therapy. Approximately 50% of patients with metastatic cancer die within three years after initial diagnosis, and 75% of such patients die within five years after diagnosis. Continuous supplementation with the compounds of the present invention may be used to prevent or reverse this potentially metastasispermissive State.

(iii) Chemotheraov

While chemotherapy has been successful in treating some forms of cancer, it has shown slight therapeutic value in treating prostate cancer where it is generally reserved as a last resort. Accordingly, the opportunity to treat prostate cancer by combining chemotherapy with the methods of the present invention will be rare. When combined, however, such treatments should be more effective than chemotherapy alone in controlling prostate cancer.

(iv) Immunotherapv

The compounds of the present invention may also be used in combination with monoclonal antibodies to treat prostate cancer. Such combined 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 celi membrane-specific anti-prostate antibody.

The present invention may also be used with immunotherapies based on polyclonal or monoclonal antibodyLV 12253

-79derived reaģents. Monoclonal antibody-derived reaģents are preferred. These reaģents are well known in the art, and include radiolafaelled monoclonal antibodies such as monoclonal antibodies conjugated with strontium-89.

(v) Crvotherapv

The methods of the present invention may also be used in conjunction with cryotherapy for treatment of prostate cancer.

Experimental Studies

The following experimental studies of compounds of the present invention and of structurally related compounds provide strong evidence that the compounds of the present invention are ncn-toxic and are effective in inhibiting NAALADase activity, treating glutamate abnormalities and treating prostate diseases.

Ir. Vivo Toxicitv of NAALADase Inhibitors

To examine the toxicological effect of NAALADase inhibition in vivo, a group of mice were injected with 2(phosphonomethyl)pentanedioic acid, a NAALADase inhibitor of high activitv, in doses of 1, 5, 10, 30, 100, 300 and 500 mg/kg body weight. The mice were subsequently observed two times per day fcr 5 consecutive days. The survival rāte at each dose Ievel is provided in TABLE II below. The results show that the NAALADase inhibitor is non-toxic to mice, suggesting that the compounds of the present invention would be similarlv ncr.-toxic to humāns when administered at therapeutically effective amounts.

-80TABLE II

TOXICOLOGICAL EFFECTS OF NAALADASE INHIBITORS
Dose (mg/kg)	1	5	10	30	100	300	500
Survival Rāte After 5 davs (%)	100	100	100	100	100	100	66.7

In Vitro Assav of NAALADase Activitv

The follovving compounds vvere tested for in vitro inhibition of NAALADase activity. The results are provided in Tables III (a) , III(b), and III (c) belovv.

TABLE III(a)

IN VITRO ACTIVĪTY OF NAALADASE INHIBITORS

Compound (nM)

-(phosphonomethyl)pentanedioic acid 0.275 + 0.08

2-(phosphonomethyl)succinic acid 70 0.0 0 + 67.3

-[[2-carboxyethyl)hydroxyphosphinyl]methyl]pentanedioic acid) 1.89 + 0.19

-(phosphonomethyl)pentanedioic acid shovved a high Ievel of NAALADase inhibiting activity, vvith a K_t of 0.27 nM (Table III(a)). The activity of this compound is >1000 times more potent than that of previously described inhibitors. Since 2(phosphonomethyl)pentanedioic acid is similar in structure to the compounds of the present invention, the results suggest that the compounds of the present invention vvould also be potent NAALADase inhibitors. By comparison, 2(phosphonomethyl)succinic acid exnibits much lovver NAALADase

-81inhibiting activity, suggesting that a glutamate analog attached to the phosphonic acid contributes to its NAALADase inhibiting activity. The results also shovv that 2-[(2carboxyethyl)-hydroxyphosphinyl]methyl]pentanedioic acid, vvhich has an additional carboxylic acid side chain similar to the aspartate residue found in NAAG, exhibits a lovver NAALADase inhibiting activity than 2-(phosphonomethyl)pentanedioic acid.

Table III (b)

Other compounds demonstrating inhibition of NAALADase activity are set forth belovv in Table III (b) . Results of the nine compounds in Table III(b) shovvs the remarkable Ki activity of a variety of compounds of the present invention.

These compounds shovv NAALADase inhibitory ability vvherein Rl comprises an aliphatic group, a aliphatic vvhich is substituted, an aromatic group, and aromatic vvhich is substituted.

-82Table III(b)

In vicro Activity of NAALADase Inhibitors

Ki(nM)

COMPOUND

231

532

148

ΛΛ.

o

-p

OH o

-p

OH

COzH

1100

f P COzH

COiH

190

148

OH

Further results, provided in Table III(c), show the remarkable Ki activity of the compounds cf the present invention. These compounds show NAALADase inhibition vvherein

Rl comprises a subscituted aliphatic (benzyl) vvhich is furthe substituted.

-83Table III(c) in vitro Activity of NAALADase Inhibitors

Ki Value (nM)

Compound

Ki - 68oM

Ki - 70nM

Ki -90nM

Ki - 175nM

COOH

Ki - 38uM

-84Protocol for In Vitro Assav of NAALADase Activitv

The amount of [³H]Glu liberaced from [³H] NAAG in 50 mM Tris-Cl buffer vvas measured for 15 minūtes at 37° C using 30-50 /ig of synaptosomal protein. Substrate and product vvere resolved by anion-exchange liquid chromatography. Duplicate assays vvere performed so that no more than 20% of the NAAG vvas digested, representing the linear range of peptidase activity. Quisquaiate (100 μΜ) vvas included in parallel assay tubes to confirm the specificity of the measurements.

In Vitro Assav of NAALADase Inhibitors on Cancer

Referring novv to FIGS. 1 and 2, the effect of NAALADase inhibitors on cancer celi line vvere examined. LNCAP celis (a prostate cancer celi line) vvere treated vvith quisqualate acid (in concentrations ranging from 10 nM tc 1 μΜ) and 2(phosphonomethyl)pentanedioic acid (in concentrations ranging from 100 pM to 10 nM). The 3H-thvmidine measurement for each concentration of quisqualate acid and 2(phosphcnomethyl)pentanedioic acid is also provided in TABLE IV belovv. FIGS. 1 and 2 present this data graphically and particularly illustrate the decrease in proliferation and thymidine uptake of celis treated vvith NAALADase inhibitors.

-85TABLE IV

Dose

3H-Thvmidine Incoraoration (dom/vvell

Ouiscrualic Acid

2-(ohosphonomethvl) pentanedioic acid

Control	4813		572	4299	+.	887
10 pM				3078	+_	1006
100 pM				2062		595
1 nM	3668	_+	866	1001		52
10 nM	2137		764	664	u.	366
100 nM	1543	+	312
1 μΜ	1295	_+	181		—

The results show that LNCAP celi proliferation (as measured by the incorporation of 3H-thymidine) decreased significantly as the concentration of the NAALADase inhibitors increased, suggesting that the compounds of the present invention would be effective in treating cancer, particularly prostate cancer.

Protocol for In Vitro Cancer Assav Celis in RPMI 1640 medium containing 10% Fetal Calf Serum (FCS) are plated in 24 vvell plates and allovved to adhere for 24 hours before addition of quisqualic acid (10'⁹ M to 10‘^s M) or 2-(phosphonomethyl) pentanedioic acid (10'^li M to 10'⁸ M) for 7 days . On the 7th day, the celis are pulsed vvith 3Hthymidine for 4 hours, harvested and measured for radioactivity. Values represent means +/- SEM of 6 separate celi vvells for each treatment. Ali experiments are performed

-86at least tvvice.

Te control for non-specific cytostatic effects of quisqualate acid and 2-(phosphonomethyl)pentanedioic acid, the aģents are simultaneously evaluated on a non-NAALADase containing prostate celi line, DU145 (Carter et al., Proc. Nati. Acad. Sci. USA, (93) 749-753, 1996). If the treatments vvith quisqualate acid and 2 - (phosphonomethyl)pentanedioic have no signifieant effect on celi grov/th, the NAALADase inhibiting activity of the aģents are uniquely responsible for their cytostatic effects cn NAALADase containing prostate carcinoma celi iines.

Celi Lines and Tissue Culture

LNCAP celis are obtained from Dr. William Nelson at the

Johns Hopkins School of Medicine in Baltimore, MD. DU145 celis are obtained from American Type Culture Collection (Rockville, MD) . Celis are grovvn in RPMI-1640 media supplemented vvith 10% heat - inactivated fetal calf serum, 2 mMglutamine, 100 units/ml penicillin, and 100 /ig/ml streptomycin (Paragon) in a humidified incubator at 37°C in a 5% CO₂/95% 0₂atmosphere.

[3H] Thvmidine Incorporation Assavs

The celis are suspended at 1 χ 10³ cells/ml in RPMI-1640 media and seeded into 24-vzell plates at 500 μΐ per vvell.

After 24 hours, various concentrations of quisqualic acid (Sigma) or the potent NAALADase inhibitor 2(phosphonomethyl) pentanedioic acid (synthesized according to the methods of Jackson et ai., J Med Chem 39(2) 619-622) is added to the vvells and the plates are recurned to the

-87incubator. On days 3, 5 and 7, media and drug are refreshed. On the 8th day following seeding, each well is pulsed with 1 μθί ³H-thymidine (New England Nuclear) for 4 hours. Media is then removed ar.d the wells washed 2 times with phosphate buffered saiine (pH=7.4). The contents of each well is subsequently solubilized with 250 μΐ of 0.2 N NaOH and transferred to scintillation vials. 5 ml UltimaGold (Packard) scintillation cocktail is added and radioactivity is guantitated using a Beckman LS6001 scintillation counter.

The puritv and/or identity of ali svnthetic compounds is ascertained by thin layer chromatograph'/, High Pressure Licuid Chromatography (HPLC), mass spectrometry, and elemental analysis. Proton Nuclear Magnetic Resor.ance (NMR) spectra are obtained using a Bruker spectrometer. Chemical shifts are reported in pāros per million relative tc tetramethylsilane as internai Standard. Analytical thin-layer chromatography (TLC) is conducted on prelayered silica gel GELF plates (Analtech, Newark, DE). Visualization of the plates is accomplished by using UV light, phosphomolybdic acid-ethanol, and/or iodoplatinate charring. Flash chromatcgraphy is conducted on Kieselgel 60, 230-400 mesh (E. Merck, Darmstadt, West Germany). Solvents are either reaģent or HPLC grade.

Rēactions are run at ambient temperature and under a nitrogen atmosphere unless otherwise noted. Solutions are evaporated under reduced pressure on a Buchi rotarv evaporator.

In vivc LNCaP Tumor Xenocraft Assav and Results

Rererring now to FIGS. 3 and 4, LNCaP human prostate cancer

-88cells were injected subcutaneously into the right flank of male nude mice. 2-(phosphonomethyl)pentanedioic acid, a NAALADase inhibitor, was administered by daily intratumoral injection (0.25 /xg/day) beginning when the tumors reached a voiume of approximately 50-70 mm³. An additional group was included using a Silicon polymer containing 2- (phosphonomethyl) pentanedioic acid v/hich released approximately 0.25 /ig/day of drug locally into the tumor. The 2 -(phosphonomethyl)pentanedioic acid polymer was changed two times per week. Tumor volumes were monitored for 42 days after the beginning of treatment.

EXPERIMENTAL PROCEDURES

Celi Lines

LNCaP is a human prostate cancer celi line that was established in 1973 from a pleural effusion of a patient who had been treated with 5-FU, doxorubicin, mechotrexate, and CTX in the 3 months before the celi line was initiated. This line is androgen receptor positive and has been used in screening anticancer drugs that are targeted as hormone antagonists. LNCa? was grown in RPMI with 1.5 g NaHCO3/L, 10% fetal bovine serum (FBS), and 2 mM L-glutamine and was ķept at 37°C in a humidified 5% CO₂/O₂ incubator. Antibiotics wers not added co the medium.

Animal Tumor Modei

NCr nude (nu/nu) male mice, age 4-5 weeks, were purchased from Taccnic (Germantown, NY). The animals were housed four per cage in sterile filter-topped cages in a ventilated cage rack. Upon arrival, they were quarantined for four working days befors

-89use. Temperature was maintained at 72 ± 5°F and relative humidity at 35-70%, and a 12-hr light/dark cycle is used. The mice vvere fed sterile, autoclavable, certified Purina rodent chovv ad libitum. Drinking vvater vvas acidified and autoclaved, and the source vvater vvas recirculated, deionized, UV-treated, and 5-μπι filtered.

After the animals vvere released from quarantine, the mice vvere injected subcutaneously in the right flank vvith 1 X 10’ LNCaP celis in Matrigel™ (0.1-ml injection volume). Tumor dimensions and body vveight vvere measured tvvice weekly. Vernier calipers vvere used to measure tumors in three planēs, and tumor volume (V) vvas calculated as follovvs: V = π(χ X y X z)/6, vvhere x, y, and z vvere the tumor measurements minus skin thiekness. At the end of the experiment, the mice vvere sacrificed by C0₃inhalation follovved by cervical dislocacion.

Pharmaceuticals

2- (phospnonomethyl) pentanedioic acid vvas made up in vvater at a concentration of 2.5 mg/ml. ?olymer containing 2(phosphonomethyl)pentanedioic acid vvas made up by grinding 140 mg NaCI to a fine povvder then mixing vvith 5mg 2(phosphonomethvl)pentanedioic acid and 350 mg silicone gel. The mixture vvas spread to a thin film and allovved to dry for 24 hours. The material vvas cut into 1-1.5 mg pieces for subcutaneous implantation.

Treatment Protocol

When the tumor volumes reached a predetermined size (mean

-90tumor volume 50-70 mm³) , mice vvere added randomly inzo treatment groups of six to eight mice each. Ali treatments vvere administered daily for at least 4 vveeks. 2(phosphonomethvl)pentanedioic acid vvas administered intratumorallv daily in a volume of 0.05 ml containing 0.025 μg 2 - (phosphonomethvl)pentanedioic acid per injection.

Polymer containing 2-(phosphonomethyl)pentanedioic acid (10 μ9 drug/mg polvmer) vvas implanted subcutaneously. Mice were anaesthetized vvith metafane, and a smail (<2mm) incision vvas made near the tumor site. Follovving implantanion, the incision vvas closed vvith a wound clip. Polymer vvas replaced tvvice weekly.

The tumor vvere measured tvvice weekly for at least 8 vveeks after the first treatment. The mean tumor volume for each group vvas calculated for each time point. Comparisons betvveen groups at specific times vvere made using an unpaired, tvvo-tailed t-test, and the results vvere analyzed using analysis of variance (ANOVA) .

Systemic toxicity was assessed from reductions in body vveight after treatment. The mice vvere sacrificed at the end of the follow-up period, or earlier if their tumor volumes reached 1600 mm³ or the tumors ulcerated.

Statistical Analysis

Statistical analysis as described above vvas performed using JMP (SAS Institūts Inc., Cary, NC)

In vivo Rat Dunnina R3327 Modei

Referring now to FIGS. 5 and 6, Dunning R3327-G prostate cancer celis vvere injected subcutaneously into both flanks of

-91syngeneic male rats. In the first study, the anti-tumor grovvth activity of 2-(phosphonomethyl)pentanedioic acid vvas tested follovving daily subcutaneous injections of the drug (1,3 10 and 30 mg/kg). 2-(phosphonomethyl)pentanedioic acid injections and tumor measurements vvere continued for 12 vveeks. In the second study, the anti-tumor grovvth activity of 2[ (phenylmethyl) hydroxyphosphinyl] methyl] pentanedioic acid vvas tested follovving daily intra-tumoral injections of the drug (0.1,1,10,100 gg) after the tumor reached an initial volume of

80-290 mm³. Tumor volumes vvere subsequently monitored for 42 days after the beginning of drug treatment.

EXPERIMENTAL PROCEDURES

Celi Lines

R3327-G is a celi line derived from an androgen-sensitive papillary adenocarcinoma derived from a spontaneouslv forming tumor in the rat prostate. R3327-G celis vvere grovvn in RPMI, 10% fetal bovine serum (FBS) , 2 mM L-glutamine, and 10-8 M dexamethasone. Cultures vvere ķept at 37°C in a humidified 5%

CO₂/O₂ incubator. Antibiotics vvere not added to the medium.

Animal Tumor Mcdel

Copenhagen male rats, age 8-10 vveeks, vvere purchased from Harlan Sprague Dawley (Indianapolis, IN) . The animais vvere housed tvvo per cage. Upon arrival, they vvere quarantined for four vvorking davs before use. Temperature vvas maintained at 72 ± 5°F and relative humidity at 35-70%, and a 12-hr light/dark cycle vvas used. The rats vvere fed certified Purina rodenc chow

-92and wa:er ad libicum.

After the animals were released from quarantine, the rats vvere ir.jected subcutaneously in both flanks with 1 χ 10⁷ R3327-G celis (O.l-ml injection volume). Tumor dimensions and body vveight were measured twice weekly. Vernier calipers vvere used to measure tumors in three planēs, and tumor volume (V) vvas calculated as follovvs: V = π(χ X y X z)/6, vvhere x, y, and z vvere the tumor measurements minus skin thickness. Tumors began to appear 4-5 vveeks after tumor celi injection. At the end of the experiment, the rats vvere sacrificed by CO₂ inhalation.

Pharmaceuticals

-(phosphcnomethyl)pentanedioic acid vvas made up in physiological saline fresh each day prior to injection. A stock solution of 2 - [ [ pheny1methy1) hydroxyphosphiny1] methyl] pentanedioic acid vvas made up in vvater at a concentration 2.5 mg/ml; ten-fold serial dilutions vvere made fresh weekly for injections.

Treatment Protocol

Zn the 2 -(phosphonomethyl)pentanedioic acid study, the rats vvere given daily subcutaneous injections of drug beginning the 14 davs follovving tumor celi implantation and continued for 12 vveeks. In the 2 - [ [phenylmethyl) hydroxyphosphinyl] methyl] pentanedioic acid study, the drug was not administered until the tumor volumes reached a predetermined size (mean tumor volume 90290 mm³) . At this time, the rats vvere divided into treatment groups cf five rats each. Ali treatments of 2LV 12253

-93((phenylmethyl) hydroxyphosphinyl] methyl] pentanedioic acid vvere subseguently administered intra-tumorally daily for 6 vveeks.

The tumors were measured tvvice weekly. The mean tumor volume for each group vvas calculated for each time point. Comparisons betvveen groups at specific times vvere made using an unpaired, tvvo-tailed t-test, and the results vvere analyzed using analyzed of variance (ANOVA) . For the 2[ [phenylmethyl) hydroxyphosphinyl] methyl] pentanedioic acid study, individual tumor volumes (V) vvere expressed as a fraction of the tumor volume on Day 0, the first day of treatment (V0) . For each group, the mean of the ratio V/VO vvas plotted as a function of time after treatment.

Statistical Analysis

Statistical analysis as described above vvas performed using JMP (SAS Institūts, Inc. Cary, NC).

EXAMPLES

The follovving examples are illustrative of preferred embodiments of methods of use and preparation of compounds of the invention and are not to be construed as limiting the invention thereto. Unless othervvise indicated, ali percentages are based upon 100% of the final formulations.

EXAMPLE 1

Preparation of 2- Γ (methvlhvdrozvp'nosphinvl)methvlļ pentanedioic acid

Scheme IV R=CH3,Rl=CH2Ph

-94Methyl-0-benzylphosphinio acid

Dichloromethylphosphite (10.0 g, 77 mmol) in 8 0 mL of dry diethyl ether was cooled to -20°C under an atmosphere of nitrogen. A solution cf benzyl alcohol (23 g, 213 mmol) and triethylamine (10.2 g, 100 mmol) in 40 mL of diethyl ether vvas added dropvvise over 1 hour while maintaining an internai temperature range of 0°C to 10°C. Once addition was complete the mixture vvas warmed to room temperature and stirred overnight. The mixture was filtered and the solid cake vvashed vvith 200 mL of diethyl ether. The organics vvere 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 vvith a 1:1 hexane/ethyl acetate to ethyl acetate gradient. The desired fractions vvere collected and evaporated to give methyl 0benzylphosphinic acid (1, R=CH3, Rl=CH2Ph,6.5 g, 50%) as a clear and colorless oil. Rf 0.1 (1:1, Hexane/EtOAc).

NMR (<36-DMSO) : 7.4 ppm (m,5H), 7.1 ppm (d, 1H) , 5.0 ppm (dd,2H), 1.5 ppm (d,3H)

2,4-Di (benzvloxvcarbonvl) butvl (methvl) - 0-benzvlahosnhinic acid

Methyl-'O-benzylphosphinic acid (3.53 g, 20.7 mmol) in 200 mL of dichloromethane was cooled to -5°C under an atmosphere of nitrogen. Triethylamine (3.2 g, 32 mmol) was added via syringe follovved by trimethylsilyl chloride (2.9 g, 27 mmol) . The reaction mixture vvas stirred and vvarmed to room temperature over 1 hour. Dibenzyl 2-methylenepentanedioate (2, 6.0 g, 18.5 mmol) in 10 mL of dichloromethane vvas added. The mixture vvas then stirred at room temperature overnight. The reaction mixture was

-95cooled to 0°C and trimethylaluminum (9 mL, 18 mmol, 2.0 M in dichloromethane) was added. The flask was warmed and stirred for 72 hours. The clear light yellow solution was cooled to 5°C and guenched by the slow addition of 5% hydrochloric acid. The guenched reaction mixture was warmed to room temperature and the organic layer removed. The organic layer was washed with 5% hydrochloric acid and with water. The organics were dried (MgSOj and evaporated under reduced pressure to give 8 g of a clear light yellow oil. The oil was purified on silica gel and eluted with a gradient of 1:1 hexanes/ethyl acetate to 100% et’nyl acetate. The desired fractions were collected and evaporated to give 2,4-di(benzyloxycarbonyl)buty(methyl)-0-benzylphosphinic acid (3,R=CH3,Rl=CH2Ph 0.8 g, 8%) as a clear and colorless oil. Rf 0.5 (ethyl acetate).

NMR (CDClj) : 7.4 ppm (m, 15H) , 5.1 ppm (m, 6H) , 3.0 ppm (m, IK), 2.4 ppm (m,3H),2.1 ppm (m,3H), 1.5 ppm (dd,3H)

Elemental Analvsis Calculated C_2eH₃₁O_iP . 0.5H₂O : C 68.01,H 6.32

Found: C 66.85,H 6.35

2-f(Methvlhvdrcxvūhosohinvl·)methvl]pentanedioic acid

2,4-di fbenzyloxycarbonyl)buty(methyl)-0-benzylphosphinic acid (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 over a pad of Celite and evaporated at high vacuum to give 2((methylhydroxyphosphinyl)methyl]pentanedioic acid (4, R=CH3,0.28 g, 78% as a clear and colorless viscous oil.

²K NMR (D,O) : 2 . 5 ppm (m, IH) , 2.2 ppm (t, 2K) , 2.0 ppm (m, IH) , 1.7 ppm(m,3H), 1.3 ppm (d, 3H)

-96Elemental Analysis Calculated C₇H₁₃0_SP.0.2 H₂O: C36.92 H 5.93

Found: C37.06 H 6.31

EXAMPLE 2

Preparation of 2 -f(butvlhvdroxyphosphinvl)methvll pentanedioic acid

Scheme IV R=n-butyl, R1=H

Butylphosphinic Acid

Diethyi chlorophosphite (25g, 0.16mol) in 60 mL of dry ether vvas cooled to 0°C under an atmosphere of nitrogen. Butylmagnesium chloride (80 mL, 0.16 mol, 2.0 M solution in ether) vvas added dropvvise over a period of 2 hours vvhile maintaining the internai temperature at O’C. Once addition was complete the thick vvhite slurry vvas heated to 30°C for 1 hour. The suspension vvas filtered under a nitrogen atmosphere and the fiitrate evaporated under reduced pressure. The clear light vellovv liquid vvas then brought un in 15 mL of vvater and stirred at room temperature. Concentrated hydrochloric acid (0.5 mL) vvas then added and an exothermic reaction vvas observed. The mixture vvas stirred an additional 15 minūtes and ezcracted vvith tvvo 75 mL portions of ethyl acetate. The organics vvere combined, dried (MgSO₄) and evaporated to give a clear and colorless liquid. The liouid vvas treated vvith NaOK (40 mL, 20 M) and stirred for 1 hour. The mixture vvas then vvashed vvith diethyl ether and acidified to pH 1.0. The desired material vvas extracted from the acidified extracc vvith tvvo 100 mL portions of ethyl acetate. The organics vvere

-97combined, dried (MgSOJ and evaporated under reduced pressure to give butylphosphinic acid (1,R=n-butyl, R1=H, l0g,51%) as a clear and colorless liquid.

IH NMR (d6-DMSO): 6.9 ppm(d, IH), 1.6 ppm(m,2H), 1.4 5 ppm(m,4H), 0.9 ppm(t,3H)

Butvl(2,4-di(benzvloxvcarbonvl)butvl1ohosohinic acid

Butylphosphinic acid {2.0g, lSmmol) in 80 mL of dry dichloromethane vvas cooled to 0^cC under an atmosphere of nitrogen. Triethylamine (6.7 g, 66 mmol) vvas added follovved by trimethylsilyl chloride (58 mL, 58 mmol, 1.0 M in dichloromethane) . The mixture vvas stirred at 0°C for 10 minūtes and dibenzyl 2-methylenepentanedioate (2)(6.4 g, 20 mmol) in 20 mL of dichloromethane vvas added. The cold bath was removed and the reaction vvarmed to room temperature and stirred overnight. The mixture vvas then cooled to 0°C and quenched by the slovv addition of 5¾ hydrochioric acid. The dichloromethane layer vvas then removed and vvashed wich 5% hydrochloric acid and vvith brine. The organic layer vvas dried (MgSOj and evaporated to give a clear light golden liquid.

The liquid vvas purified by flash chromatography and eluted vvith 3:1 hexane/ethyl acetate containing 5¾ acetic acid. The desired fractions were combined and evaporated to give butyl[2,4-di(benzyloxycarbonyl)butyl]phosphinic acid (3,R=n25 butyl, R1=H) (2.9 g, 40%) as a clear and colorless oii.

Rf0.12 (3:1, Hex./EtOAc 5% AcOH).

NMR (d6-DMSO): 7.3 ppm (m, 10), 5.0 ppm (s,4H), 2.7 ppm (m, IH) 2.3 ppm (y, 2H), 1.8 ppm (m, 2H), 1.3 ppm (m, 4H), 0.8 ppm

-98(t, 3H)

2- Γ (ButYlhvdroxvohosūhinvl)methvllpentanedioic acid

Butyl [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 on a Parr hydrogenator at 40 psi for 4.5 hours. The mixture vvas filtered through a pad of Celite and evaporated under high vacuum to give 2[ (butylhydroxyphosphinyl) methyl] pentanedioic acid (4, R=nbutyl)(0.75 g, 43%) as a clear and colorless viscous oil.

NMR (D₂0): 2.4 ppm (m, 1H), 2.1 ppm (t, 2H), 1.9 ppm (m,

1H), 1.6 ppm (m, 3H), 1.4 ppm (m, 2H), 1.1 ppm (m, 4H), 0.6 ppm (t, 3H)

Elemental Analysis Calculated 0.5 H₂O: C 43.64, H

7.32: Found C 43.25, H 7.12

EXAMPLE 3

Preparation of 2-i(benzvlhvdroxvphosphinvl)methvl)pentanedioic acid

Scheme IV R=CH2Ph, R1=H

Benzylohosohinic acid

Diethylchlorophosphite (25 g, 0.16 mol) in 100 mL of dry diethyl ether vvas cooled to O°C under an atmosphere of nitrogen. Benzylmagnesium chloride (80 mL, 0.16 mol, 2.0 M solution in Et₂O) vvas added dropvvise over tvvo hours vvhile maintaining a temperature belovv 10°C. A thick vvhite slurry formed and stirring was continued at room temperature for 1

-99hour. The mixture was filtered under a nitrogen atmosphere and the filtrate evaporated under reduced pressure to give a clear and colorless liguid. The liguid was stirred as 15 mL of water was added followed by 0.5ml concentrated hydrochloric acid. An exothermic reaction was observed and stirring was continued for an additional 30 minūtes followed by extraction with ethyl acetate. The organics were combined, washed with brine, dried (MgSOj and evaporated. The clear light golden liquid was added to sodium hydroxide (50 mL, 2.0 M NaOH), stirred for one 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 (MgSOj and evaporated to give benzylphasph.in.tc acid (1, R=CH2Ph, Rl+H) (8 g, 3 2%) as a clear light golden oil.

^XH NMR (<J6-DMSO): 7.3 ppm (m, 5H) , 6.9 ppm (d, 1H) , 3.1 ppm (d, 2H)

Benzvl Γ2,4-di (benzvloxvxcarbonvl) butvll phosphinic acid

Benzylphosphinic acid (2.3 g, 15 mmol) in 150 mL of dry dichloromethane was cooled to 0°C under a nitrogen atmosphere. Triethylamine (6.5 g, 65mmol) was added followed by trimethylsilyl chloride (5.8 g, 54 mmol) while the reaction temperature was maintained at 0°C. After 30 minūtes diber.zvl 2-methylenepentanediote (2) in 20 mL of dichloromethane was added over 5 minūtes. The reaction mizture was left to warm to room temperature and stirred overnight. The clear soiution was cooled to 0°C and guenched with 5% hydrochloric acid and

-100vvith brine, dried (MgSOJ and evaporated to give a clear yellow liquid. Purification by flash chromatography and elution vvith 1:1 hexane/ethyl acetate containing 10% acetic acid yielded 2.0 g (28%) of benzyl(2,4di(benzyloxycarbonyl)butyl]phosphinic acid (3, R=CH2Ph, Rl+H) as a clear light yellovv oil. Rf 0.37 (i:i Hex./EtOAc,

10%AcOH).

^lH NMR (d5-DMSO): 7.2 ppm(m,15H), 5.0 ppm(s,4H),3.0 (d,2H),2.8 ppm(m,1H),2.3 ppm(t,2H), 1.9 ppm(m,2H), 1.7 ppm(t,lH)

2-f(Benzvlhvdroxvphosphinvl)methvlToentanedioic acid

Benzyl (2,4-di(benzyloxcarbonyl)butyl]phosphinic acid(0.5 g,

1.0 mmol) in 20 mL of vvater containing 120 mg of 10% Pd/C vvas hydrogenated on a Pāri hydrogenator at 40 psi for 6 hours. Filtration through a Celite pad follovved by evaporation on high vacuum gavē 0.17 g (57%) of 2[(benzylhvdroxyphosphinyl)methyl]pentanedioic acid(4,R=CH2Ph) as a vvhice solid.

1H NMR (D₂O): 7.1 ppm(m,5H), 2.9ppm(d,2H), 2.4ppm(m,1H),

2.lppm(t,2H), 1.8ppm(m,1H), 1.6ppm(m,3H)

Elemental Analysis, Calculated C₁₃H₁₇O₅P: C52.00H5.71: Found: C51.48H5.70

EXAMPLE 4

Preparation of 2fphenvlethvlhvdroxvphosphinvl)methvl 1 pentanedioic acid

Scheme IV R=Ch2CH2Ph,R1=H

-101Phenethvlohosohinic acid

Diethylchlorophosphite (15.6 g,0.i mol) in 100 mL of dry diethyl ether vvas cooled to 5°C under an atmosphere of nitrogen. Phenethylmagnesium chloride (100 mL, 0.1 mol, 1.0 M in THF) vvas added dropvvise over 2 hours while maintaining a temperature betvveen 0-10°C. A thick vvhite slurry formed and stirred at room temperature overnight. The mixture vvas filtered under a nitrogen atmosphere and the filtrate evaporated under reduced pressure to give a clear and colorless liquid. The liguid vvas stirred as 15 mL of vvater vvas added follovved by 0.5 mL of concentrated hydrlochloric acid. An exothermic reaction vvas observed and stirring continued for 15 minūtes follovved by extraction vvith ethyl acetate. The organics vvere combined, vvashed vvith brine, dried (MgSOJ and evaporated. The clear liquid vvas brought up in sodium hydroxide (40 mL, 2.0 M NaOH), stirred for 1 hour and washed once vvith diethyl ether. The aqueous layer vvas acidified to pH 1.0 vvith concentrated hydrochloric acid and extracted vvith ethyl acetate. The organics vvere combined, dried (MgSO₄) and evaporated to give phenethylphosphinic acid (1,R=CH2CH2Ph, R1=H)(9.8 g, 58%) as a clear light yellow oil.

^lH NMR (d6-DMSC) :7.2 ppm (m,5H), 6.9 ppm (d,lH), 2.8 ppm (m,2H), 1.9 ppm (m,2H)

2,4-Di(benzvlcxvcarbonvl)butvl(phenethvl)ohosohinic acid

Phenethylphosphinic acid (l.Og, 5.9 mmol) in 50 mL of dry dichloromethane was cooled to -5°C under a nitrogen

-102atmosphere. Triethylamine (2.3g, 23 mmol) vvas added follovved by trimethylsilvl chloride 2.2 g, 21 mmol) vvhile the reaction temperature was maintained at 0°C. After 10 minūtes dibenzyl 2-methvlenepentanedioate (2) in 10 mL of dichloromethane vvas added over 10 minūtes. The reaction mixture vvas left to vvarm to room temperature and stirred overnight. The clear solution vvas cooled to 0°C and guenched vvith 5% hydrochloric acid follovved by removal of the organic layer. The organic layer vvas vvashed vvith brine, dried (MgSO4) and evaporated to give a clear light golden liguid. Purification by flash chromatography and elution vvith 1:1 Hexane/EtOAc containing 5%

AcOH resuiced in 1.2g (41%) of 2,4di (benzyloxycarbonyl) butyl (phenethyl) phosphir.ic acid(3,R=CH2Crf2Ph,R1=H) as a clear and colorless oil.

¹H NMR (<35 - DMSO) : 7.2 ppm (m, 15H) ,5.0 ppm (s , 4K) ,3.3 ppm (m, 1H) , 2.8 ppm(m,4H), 2.3 ppm(m,2), 1.8 ppm(m,4K)

2,4-Γf?henethvlhvdroxvūhosphinvl)methvlloentanedioic acid

2,4 -Di ‘.'benzyloxycarbonyl) butvl (phenethyl) phospninic acid (1.1 g,2.2 mmol·) in 20 mL of vvater containing 120 mg of 10% Pd/C vvas hvdrogenated on a Parr hydrogenator at 40 psi overnight. Filtration through a Celite pad follovved by evaporation cn high vacuum gavē 0.8 g (114%) of 2((phenethylhydroxyphosphinyl)methyl]pentanedioic acid (4 , R=CH2CK2Ph) as a vvhite solid.

’-H NMR iD,O) : 7.2 ppm (m, 5H) , 2.7 ppm (m, 2K) , 2.5 ppm (m, 1H) ,

2.3 ppm (t,2H), 1.9 ppm (m,5H), 1.5 ppm (t,lH)

Elemental Analvsis:

-103Calculated C₁₄H₁₉O_SP 0.75H₃0,0.5 AcOH: C 50.3 5 H 6.34 Found: C 50.26 H 5.78

EXAMPLE 5

Preparation of 2-Π3phenvlproovlhvdroxvoho5PhinvD methvl]pentanedioic acid

Scheme IV R=CH2CH2CH2Ph, R1=H

3-Phenvloroovlphosphinic acid

Magnesium turnings (2.44 c, 0.10 mol) in 20 mL of dry aiethyl ether under an atmosphere of nitrogen vvas added several iodine crystals. Phenylpropyl bromide (20.0 g, 0.10 mol) in 80 mL of diethvl ether vvas placed in a dropping funnel. Approximately 10 mL of the bromide soluoion vvas added to the magnesium turnings and stirring vvas initiated. After several minūtes the iodine vvas consumed and additional nhenyipropyl bromide vvas added vvhile maintaining a temperature of 3 5°C. Once additional vvas complete (1.5 hours) the mixture vvas sealed and stored at 5°C.

Diethylchlorophosphite (15.7 g, 0.1 mol) in 50 mL of dry diethyl ether was cooled to 5°C under an atmosphere of nitrogen. Pher.ylpropylmagnesium bromide (100 mL, 0.1 mol, 1.0 M solution of in Et_zO) vvas added dropvvise over 2 hours vvhile maimaining a cemperature betvveen 0-10°C. A thick vvhite slurry formed and was stirred an additional 30 minūtes. The mixture vvas filcered under a nitrogen atmosphere and the filcrate evaporated under reduced pressure to give a clear and colorless liguid. To the liguid vvas added 20 mL of vvater

-104followed by 0.5ml of concentrated hydrlcchloric acid. An exothermic reaction was observed and stirring continued for 20 minūtes followed by extraction with ethyl acetate. The organics were combined, washed with brine, dried (MgSO„) and evaporated. To the ciear liquid was added sodium hydroxide (40 mL, 2.0 M NaOH), the resulting solution stirred for 1 hour and then washed with diethyl ether. The agueous layer was acidified to pK 1.0 with concentrated hydrochloric acid and extracted twice with ethyl acetate. The organics were combined, dried (MgSC.) and evaporated to give 3phenylpropylphosphinic acid (1, R=CH2CK2CH2Ph,R1=H) (9.8 g, 53%) as a ciear and colorless oil.

NMR (d6 - DMSO) : 7.2 ppm (m,5K) , 6.9 ppm (d,IK) , 2.6 ppm (t.2H). 1.7 ppm (m,2H), 1.6 ppm (m,2H)

2,4-Di(benzvloxycarbonvl)butvl(3-ohenvloropvl)ohosohinic acid

3-phenylpropylphosphinic acid(1.0 g, 5.4 mmol) in 50 mL of dry dichloromethane was cooled to -5°C under a nitrogen atmosphere. Triethviamine (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 minūtes dibenzyl 2-methvlenepantanedioate (2) in 10 mL of dichloromethane was added over 10 minūtes. The reaction mixture was warmed to room temperature and stirred overnight. The ciear solution was cooled to 0°C and quenched with 5% hydrochloric acid followea by removal of the organic layer. The organic layer was was’ned with brine, dried (MgSO,) and evaporated to give a ciear yellow liguid. Purification by flash chromatography and

-105elution with 4:1 hexane/ethyl acetate containing 5% acetic acid resulted in 1.5g (56%) of 2,4di(benzyloxycarbonyl)butyl(3-phenylpropyl)phosphinic acid(3,R=CH2CH2CH2Ph, R1=H) as a clear light yellow oil. Rf

0.58 (1:1 Hex./EtOAc,5%AcOH);

’-H NMR (d6-DMSO) : 7.2 ppm (m,15H), 5.0 ppm (s,4H), 2.7 ppm (m, 1H), 2.5 ppm (m,5H), 2.2 ppm (m,2H),1.8ppm(m,3H), 1.6 ppm (m,2H)

Elemental Analysis:

Calculated C₂₃H₃₃O₅P. 1.3H,O: C 65.48 H 6.75 Found: C 65.24 K 6.39

2-Γ(3-Phenvlcropvlhvdroxvūhosphinvl)methvl)pentanedioic acid

2,4-Di(benzyloxycarbonyl)butyl(3-phenylpropyl;phosphinic acid(15)(1.4 g,2.9 mmol) in 20 mL of watsr containing 150 mg of 10% Pd/C was hydrogenated on a Parr hydrogenator at 40 psi overnighc. Filtration through a Celite pad followed by evaporation cn high vacuum gavē 0.8 g (89%) of 2-[(3phenylpropylhydroxyphosphinyl)methyl] pentanedioic acid(4,RsCH2CR2CH2Ph)as a light yellow viscous oil).

’Ή NMR (D20): 7.4 ppm (m,5H), 2.7 ppm (m,3H), 2.4 ppm (t,3H),

1.8 ppm (m,7E);

Elemental Analysis:

Calculated C.=E₂,O_SP 0.75 K₂O, 0.75 AcOE: C51.23 H 5.64 Found: C50.85 H 6.02

EKAMPLE 6

Preparation cf 2 - Γ Γ (4-metbvlbenzvl) hvdrozvp'nosphinvl)

-106methvllpentanedioic acid

Scheme V, Compound 5

Hexamethyldisilazane (21.1 mL, 100 mmol) was added to vigorously stirred ammonium phosphinate (8.30 g, 100 mmol), and the resulting suspension vvas stirred at 105 C for 2 h. A solution of 4-methylbenzyl bromiae (5.00 g, 27.0 mmol) vvas then dropvvise added to the suspension at 0°C. The mixture vvas stirred at rt for 19 h. The reaction mixture vvas then diluted vvith dichloromethane (50 mL) and vvashed vvith 1 N HCI (50 mL) . The organic iayer vvas separated, dried over Na₂SO₄, and concentrated to give 4.72 g of a vvhite solid. This vvas dissolved in dichloromethane (50 mL) and benzyl alcohol (3.24 g, 30 mmol) vvas added to the solution. 1,3Dicyclohexyicarbcdiimide (DCC) (6.19 g, 30 mmol) vvas then added to the solution at 0°C, and the suspension vvas stirred at rt for 14 h. The solvent vvas removed under reduced pressure and the residue vvas suspended in EtOAc. The resulting suspension vvas filtered and the filtrate vvas concentrated. The residue vvas purified by silica gel chromatographv (hexanes: EtOAc, 4:1 to 1:1) to give 2.40 g of 4-methylbenzyl-0-benzylphosphinic

acid	(2, R=4	-methylbenzyl) as	a vvhite solid (34%	yield):	Rf
0.42	(EtOAc;	; '-H NMR (DMSO-d₆)	delta 2.30 (s, 3 H)	1 , 3.29	(d, J
= 16 .	,6 Hz, 2	H) , 5.2 (m, 2 H) ,	, 7.0 (d, J = 543 Hz, 1 H),	Ί .1-

7.2 (m, 4 H), 7.3-7.4 (m, 5 H).

To a solution of 4-methylbenzyl-0-benzylphosphinic acid (2, R=

4-methylbenzyl) (2.16 g, 8.3 mmol) in TK? (15 mL) vvas added sodium hydride (0.10g, 60 % dispersion in oil) follovved by

-107dibenzyl 2-methylenepentanedioate at 0 C, and the mixture was stirred at rt for 4 h. The reaction mixture vvas then diluted vvith EtOAc (50 mL) and poured into IN HCI (50 mL) . The organic layer vvas separated, dried over Na₂SO,, and concentrated. This material vvas 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) -obenzylphosphinic acid (4, R = 4-methylbenzyl)as colorless oil (70% yield) : Rf 0.61 (EtOAc); ³H NMR (CDC1₃) delta 1.6-1.8 (m,

H) , 1.9-2.0 (m, 2 H) , 2.1-2.4 (m, 6 H) , 2.7-2.9 (m, 1 H) , 3.05 (dd, J = 9.0, 16.8 Hz, 2 H) , 4.8-5.1 (m, 6 H) , 7.0-7.1 (m, 4 H), 7.2-7.4 (m, 15 H).

To a solution of 2,4-di(benzyloxycarbonyl)butyl(4methylbenzyl) -o-benzylphosphinic acid (0.70 g, 1.2 mmol) in ethanol (30 mL) vvas added Pd/C (5%, 0.10 g) and the suspension vvas shaken under hydrogen (50 psi) for 18 h. The suspension vvas then filtered through a pad of Celite and concentrated under reduced pressure. The resulting residue vvas dissolved in distilled vvacer (5 mL) , passed through a column of AG 50WX8 resin (H* form), and lyophilized to give 0.21 g of 2-[[(4methylbenzyl) hydroxyphosphinyl] methyl] pentanedioic acid (5, R = 4-methylbenzyl) as a vvhite solid (55% yield) : Rf 0.62 (ί-

PrOH	:H₂O,	7:3); ^:H NMR	<D₂O)	delta 1.7-1.	9 (m, 3 H), 2.0-2.2
(m,	1 H) ,	2.33 (dt, J	= 1.7	Hz, 7.4 Hz,	2 H), 2.55-2.70 (m, I
H) ,	3.12	(d, J = 16.5	Hz, 2	H) , 7.0-7.1	(m, 2 H), 7.2-7.3 (m,
2 H)	. Anal. Calcd for	C_UH,₇O	₅P*0.30H₂O:C,	52.60; H, 6.18. Found

ο, 52.60; K, 6.28.

-108EXAMPLE 7

Preparation of 2-Γf(4-Fluorobenzvl)hvdroxyphosphinvn methvl]oentanedioic acid (R = 4-fluorobenzyl):

Scheme V, prepared as described in the above example vvhere R = methylbenzyl:

Rf 0.64 (i-PrOH:K₂O, 7:3); ^LH NMR (D₂0) delta 1.7-1.9 (m, 3 H) , 2.0-2.2 (m, 1 H) , 2.3-2.4 (m, 2 H), 2.55-2.70 (m, 1 K), 3.12 (d, J = 16.5 Hz, 2 H), 7.0-7.1 (m, 2 H), 7.2-7.3 (m, 2 H). Anal. Calcd for C₁₃H_1SFO_SP*0.25H₂O: C, 48.38 ; H, 5.15. Found: C,

48.38; H, 5.15.

EXAMPLE 8

Preparation of 2-ΓΓ(4-Methoxybenzvl)hvdroxvohosphinvl] methvilpentanedioic acid (R = 4-methoxvbenzyl):

Scheme V, prepared as described in the above example vvhere R = methylbenzyl:

Rf 0.56 (i-PrOH:K₂O, 7:3); ^LH NMR <D_:O) delta 1.8-1.9 (m, 3 H) , 2.0-2.2 <m, 1 H) , 2.3-2.4 (m, 2 H), 2.55-2.70 (m, 1 H), 3.16 (d, J = 16.7 Hz, 2 H) , 3.81 (s, 3 K) , 6.98 (d, J = 8.7 Hz, 2 H), 7.25 (d, J = 8.7 Hz, 2 H). Anal. Calcd for

C₁₄H.₉0₇P*0.30H₂O:C, 50.09; H, 5.89. Found: C, 49.98 ; H, 5.80.

ΕΧΑΜΡΕΕ 9

Preparation of 2 -ΓΓ(2-Fluorobenzvl)hvdroxvphosphinvl] methvl 1 pentanedioic acid (R = 2-fluorobenzyl) :

Scheme V, prepared as described in the above example vvhere R = methylbenzyl:

Rf 0.67 (i-PrOH:H₂O, 7:3); ^lH NMR (D₂O) deltā 1.8-1.9 (m, 3 H) ,

-1092.0-2.2 (m, 1 K) , 2.3-2.4 (m, 2 H) , 2.55-2.70 (m, 1 H) , 3.28 (d, J = 16,6 Hz, 2 H), 7.1-7.5 (m, 4 H). Anal. Calcd for C_uH₁₅FO_iP*0.10K₂0:C, 48.79; H, 5.10. Found: C, 48.84 ; H, 5.14.

EKAMPLE 10

Preparation of 2- f Γ (Pentafluorobenzvl) hvdroxvphosphinvl1 methvllpentanedioic acid (R = pentafluorobenzyl) :

Scheme V, prepared as described in the above example vvhere R = methylbenzyl:

Rf 0.69 (i-PrOH:H₂O, 7:3); 'H NMR (D₂0) delta 1.8-2.0 (m, 3 H) , 2.1-2.3 (m, 1 H;, 2.3-2.5 <m, 2 H) , 2.7-2.9 (m, 1 H) , 3.29 (d,

J = 15.4 Hz, 2 E) , Anal. Calcd for C_l3H.₂F₅O₅P*0.45H₂0 :C, 3 9.20 ;

H, 3.26. Found: C, 39.17; H, 3.28.

EXAMPLE 11

Preparation cf 2-f(methvlhvdroxvphosphinvl)methvl) pentanedioic acid Scheme VI, Compound 9

0 2,4-Di(benzyloxvcarbonyl)butylphosphinic acid (6)

Dry phosphinic acid (100 g, 1.52 mol) vvas dissolved in 100 ml of chloroform and treated vvith triethylamine (155 g, 1.52mcl) . The mixture vvas evaporated and transferred to a three liter flask, containing 750 mL of chloroform. The solution vvas stirred by means of a mechanical stirrer and the flask cooled to 0°C. The clear solution vvas treated vvith triethylamine (277 g, 2.72 mcl) follovved by trimethylsilyl chloride (281 g, 2.58 mol) . Once addition cf trimethylsilyl chloride vvas

-110complete dibenzyl 2-methylenepentanedioate (2) in 150 mL of chloroform was added dropvvise over 20 minūtes. The lovv temperature bath vvas removed and the mixture vvarmed to room temperature. After 6 hours the thick slurry vvas filtered and the fiitrate cooled to 0°C. The fiitrate vvas then quenched vvith 5% hydrochloric acid and the organic layer removed. The aoueous layer vvas extracted vvith chloroform, the organics combined, dried (MgSOJ and evaporated under reduced pressure to give 55 g of 2,4-di(benzyloxycarbonyi)butylphosphinic acid (6) as a light yellow liquid. The liquid vvas purified by flash cnromatography and eluted using 3:1 hexanes/ethyl acetate containing 5% trifluoroacetic acid to give 40 g (7%) of the desired product. Rf0.29(3:1 Hex./EtOAc 5% TFA),· ^XH NMR (CDCl,): 7.3 ppm (m, 10H) , 7.2 ppm (d, 1H) , 5.12 ppm (s,

2H) , 2.5 ppm (m, 1H) , 2.4 ppm (t, 2H) , 2.2 ppm (m, IK), 2.0 ppm (m, 3H)

2,4-Di?ben2vloxvcarbonvl)butvlbenzvlohosohinic acid (7)

To a solution of 2,4-di-(benzyloxycarbonyl)butyl phosphinic acid (6) (15.3 g, 49.4 mmol) in tetrahydrofuran vvas added benzyl alcohol (5.3 g, 49.3 mmol) and dimethylamino in tetranydrofuran was added benzyl alcohol (5.3 g, 49.3 mmol) and dimethvlamino pyridine (0.5 g). Dicylcohexylcarboaiimide (DCC, 12g, 58 mmol) vvas added and a vvhite precipitate formed.

After 30 minūtes the vvhite suspension vvas filtered and the fiitrate evaporated under reduced pressure. The clear and colorless cil vvas purified by flash chromatography and eluted vvith 1:1 Hex./EtOAc to give 2,4LV 12253

-Uldi (benzyloxycarbonyl)butylbenzylphosphinic acid (7) (11.5 g, 47%) as a clear and colorless oil. Rf. 0.16 (1:1 Hex./EtOAc); ^XH NMR (CDClj) : 7.3 ppm (m,15H), 7.2 ppm (d, IH) , 5.0 ppm (m,6H), 2.9 ppm (m,IH), 2.2 ppm (m,3H), 1.9 ppm (m,3H)

2,4 -Di(benzyloxvcarbonvl)but vlihvdroxv(chenvl) methvllbenzvlohosphinic acid (8)

2,4-Di(benzyloxycarbonyl)butylbenzylphosphinic acid (7) in 5 mL of dry THF vvas added dropvvise to a stirring cooled (0°C) mixture of sodium hydride (0.09 g, 2.3 mmol) in 15 mL of THF. After 15 minūtes benzaldehyde (0.23 g, 2,.2mmol) vvas added via syringe vvhile maintaining a temperature of 0°C. After 30 minūtes the mixture vvas quenched vvith vvater and extracted vvith tvvo portions of dichloromethane. The organics vvere combined and evaporated to give a clear colorless oil. The oil vvas chromatographed on silica and eluted vvith a 1:1 Hex./EtOAc solvent system. The desired fractions vvere collected and evaporated to give 0.4 g (33%) of 2,4di(benzyloxycarbonyl)butyl[hydroxy(phenyl)methvl]benzylphosphi nic acid (6) as a clear and colorless oil. Rf0.18(l:l Hex./EtOAc);

^lH NMR (CDClj) : 7.3 ppm (m,20H), 5.2 ppm (m,lH), 4.9 ppm (m,6H), 2.8 ppm (dm,IH), 2.2 ppm (m,3H), 1.9 ppm (m,3H)

2- ' ^fHvdroxv (oher.vl) methvl 1 hvdroxvohosphinvlmethvl) pentanedioic acid(9)

2,4 - Di(benzyloxvcarbonyl)butyl[hydroxy(phenyl) methvl]benzylphosphinic acid(6)(0.37 g, 0.6 mmol) in 25 mL of

-112water containing 0.10g of 10% Pd/C was hydrogenated at 40 psi for 6 hours. The mixture was filtered through a pad of Celite and iyophilized to give 2( [hydroxy (phenyl) methyl] hydroxyphosphinylmethyl) pentanedioic acid (9) (0.14 g, 70%) as a white solid.

‘H NMR (D2O): 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),1.9ppm(m,3H)

Element Analysis:

Calculated C₁₃H₁₇O₇P. 0.6H₂O:C 47.74 H 5.61

Found: C 47.73 H 5.68

ΕΧΑΜΡΙ,Ε 12

Preparation of Dibenzvl 2-Methvleneoentanedioate.

Scheme III.

Benzyl acrylate (500 g, 3 mol) was heated to 100°C under an atmosphere of nitrogen. The heating was stopped and HMPT (10 g, 61 mmol) was added dropwise while maintaining an internai temperature of 135-145°C. Once addition was complete the mixture was cooled to room temperature and a slurry of siiica wich 5:1 Hex/EtOAc was added. The slurry was then transferred to a column containing a plug of dry siiica. The column was then washed with 1:1 Hex/EtOAc and the solvent was collected and evaporated. The clear yellow liquid was distilled under high vacuum (200 /iHg) to give an initial fraction of 8 g distilling at 45°C and then the desired product at 180-185°C (212 g, 42 %) as a clear and colorless liauid. ^lH-NMR (CDClj)

7.3 ppm (s, 10K) ; 6.2 ppm (s, 1H) ; 5.5 ppm (s, 1H) ; 5.2 ppm

-113(s, 2H); 5.1 pcm (s,2H); 2.6 ppm (m, 4H).

ΕΧΑΜΡΡΕ 13

Preparation of Dibenzvl 2- Γ f3is (benzvloxv) Dhosphorvll methvll pentanedioate.

Scheme III

Dibenzyl phosphite (9.5g, 36mmol) in 350ml of dichloromethane was cooled to 0°C. To this stirring solution vvas added trimethyl aluminum (18.2ml, 2.OM solution in hexane, 36.4mmol). After 30 minūtes 1 (6.0g, 37 mmol) in 90 ml of dichloromethane vvas added dropvvise over 10 minūtes. The clear and eoiorless solution vvas then vvarmed to room temperature and left to stir overnight. The mixture vvas then quenched by the slovv addition cf 5% HCI. After stirring an additional 1.5 hours the lovver organic layer vvas removed and the agueous Iayer extracted once vvith lOOml of dichloromethane. The organics vvere combined, dried (MgSO₄) , and evaporated to give a clear light goiden liquid. The liquid vvas chromatographed on silica gel (4cm*30cm) and eluted vvith a gradient (4:1-1:1) solvent system (Hexane/EtOAc). The fractions containing the desired product vvere combined and evaporated to yield 2 (7.lg,

42%) as a clear and eoiorless liquid. The liquid vvas then distilled on a Kughleror apparatus at 0.5mm Hg and 195-200°C. The distillate vvas discarded and the remaining light goiden oil vvas chromatographed on silica gel (1:1, Hex./EtOAc) to give 2.9g of 2 as a clear and eoiorless oil. TLC R_; 0.5 (1:1,

Hex./EtOAc).

1H-NMR (CDClj

-1147.1-7.4 (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 (τη, 3H) .

EXAMPLE 14

Preparation of_2-(Phosphonomethvl)pentanedioic Acid.

Scheme III

The benzyl pentanedioate (2.9g, 4.9mmol) was added to a mixture of 20mi of methanol containing 0.29g (6mol%) of 10% Pd/C. This mixture was hydrogenated on a Parr hydrogenator at 40 psi for 24 hours, filtered and evaporated to give 3(1.0g, 90%) as a clear slightly golden viscous oil.

1H-NMR (D,0)

2.6-2.78(m, 1H); 2.25-2.40(m, 2H); 1.75-2.15(m, 4H).

EXAMPLE 15

A patient is diagnosed vvith adenocarcinoma of the prostate. The patient mav then be administered a NAALADase inhibitor, such as set forth in examples 1 through 3, by direct injection into the tumor. After this initial treatment, the patient may be optionally administered the same or differenc NAALADase inhibitor by intermittent or continuous adminiscracion bv subdural pump. It vvould be expected that no further occurrences of the adenocarcinoma vvould develop.

EXAMPLE 16

A patient is diagnosed vvith adenocarcinoma of the prostate. The patient may then be administered a NAALADase inhibitor, such as set forth in examples 1 through 3, by direct injection into the tumor. After this initial

-115treatment, the patient may be optionally administered the same or different NAALADase inhibitor by intermittent or continuous administration by implantation of a biocompatibie, polymeric matrix delivery system. It vvould be expected that no further occurrences of the adenocarcinoma vvould develop.

EXAMPLE 17

A patient is diagnosed vvith benign prostatic hyperplasia. The patient mav then be administered a NAALADase inhibitor, such as set forth in examples 1 through 3, bv direct injection into the tumor. After this initial treatment, the patient may be optionaliv administered the same or different NAALADase inhibitor by intermittent or continuous administration by injection, subdural pump, or polymeric matrix implant. It vvould be expected that the benign prostatic hyperplastic celis do not develop into carcinoma.

EXAMPLE 18

A patient is diagnosed vvith adenocarcinoma of the prostate. The adenocarcinoma appears not to have metastasized. The adenocarcinoma vvould be removed by surgery. After post-operative recovery, the patient vvould be locally administered NAALADase inhibitor by intermittent or continuous administration by injection, subdural pump or by polymeric matrix implant. It vvould expected that no further occurrences of the carcinoma vvould develop.

EXAMPLE 19

A patient is diagnosed vvith metastatic adenocarcinoma of the prostate. The adenocarcinoma appears to have metastasized, buc surgery stili is indicated as an effective

-116treatment modality. Tumor tissue vvould be removed by surgery. The patient vvould be locally administered a NAALADase inhibitor such as described herein from the time, approximately, of the initial diagnosis and vvould continue after surgery. After post-operative recovery, the patient vvould be maintained at this Ievel of NAALADase inhibitor by a regimen of periodic local administration. The patient vvould be monitored carefully for intolerable adverse side-effects of NAALADase inhibitor administration. It vvould be expected that no further tumors develop. If some of the original, small tumorous masses ars detected after surgerv, they vvould be expected to not grovv in size.

EXĀMPLE 20

A patient is diagnosed vvith ACTH-producing tumors. The patient may then be administered a NAALADase inhibitor, such as set forth in examples 1 through 3, bv direct injection into the tumor. After this initial treatment, the patient may be optionally administered the same or different NAALADase inhibitor by direct injection, subdural pump, or implantation of a biocompatible, polymeric matrix delivery system. It vvould be expected that tumor grovvth or tumor celi grovvth vvould be prevented or inhibited and that no further occurrences of the ACTH-producing tumor vvould develop.

EKAMPLE 21

A treatment such as that described in Example 9 vvherein the patient is diagnosed vvith acute lymphocytic ieukemia.

EXAMPLE 22

A treatment such as that described in Example 9 vvherein

-117the patient is diagnosed vvith acute non-lymphocytic leukemia.

ΕΧΑΜΡΙ,Ε 23

A treatment such as that described in Example 9 vvherein the patient is diagnosed vvith metastatic or non-metastatic cancer of the adrenal cortex.

ΕΧΑΜΡΙ,Ε 24

A treatment such as that described in Example 9 vvherein the patient is diagnosed vvith metastatic or non-metastatic bladder cancer.

ΕΧΑΜΡΙ,Ε 2 5

A treatment such as that described in Example 9 vvherein the patient is diagnosed vvith metastatic or non-metastatic brain cancer.

ΕΧΑΜΡΙ,Ε 26

A treatment such as that described in Example 9 vvherein the patient is diagnosed vvith metastatic or non-metastatic breast cancer.

ΕΧΑΜΡΙ,Ε 2 7

A treatment such as that described in Example 9 vvherein the patient is diagnosed vvith metastatic or non-metastatic cervical cancer.

ΕΧΑΜΡΙ,Ε 25

A treatment such as that described in Example 9 vvherein the patient is diagnosed vvith metastatic or non-metastatic chronic lymphocyzic leukemia,

ΕΧΑΜΡΙ,Ε 2 9

A treatment such as that described in Example 9 vvherein

-118the patient is diagnosed vvith metastatic or non-metastatic chronic myelocytic leukemia.

EXAMPLE 30

A treatment such as that described in Example 9 vvherein 5 the patient is diagnosed vvith metastatic or non-metastatic coloreccal cancer.

EXAMPLE 31

A treatment such as that described in Example 9 vvherein the patient is diagnosed vvith metastatic or non-metastatic cutaneous T-cell lymphoma.

EXAMPLE 32

A treatment such as that described in Example 9 vvherein the patient is diagnosed vvith metastatic or non-metastatic endometrial cancer.

ΕΧΑΜΡΏΕ 33

A treatment such as that described in Example 9 vvherein the patient is diagnosed vvith metastatic or non-metastatic esophageal cancer.

EXAMPLE 34

0 A creatment such as that described in Example 9 vvherein the patient is diagnosed vvith metastatic or non-metastatic Evving's sarcoma .

EXAMPLE 35

A treacmenn such as that described in Example 9 «herein the patient is diagnosed vvith metastatic or non-metastatic gallbladder cancer.

EXAMPLE 36

A nreanmenc such as that described in Example 9 vvherein

-119the patient is diagnosed with metastatic or non-mecastatic hairy celi leukemia.

EXAMPLE 37

A treatment such as that described in Example 9 wherein the patient is diagnosed with metastatic or non-metastatic head and neck cancer.

ΕΧΑΜΡΕΕ 38

A treatment such as that described in Example 9 wherein the patient is diagnosed with metastatic or non-metastatic Hodgkin's lvmphoma.

EXAMPLE 39

A treatment such as that described in Example 9 wherein the patient is diagnosed with metastatic or non-metastatic Kaposi's sarcoma.

EXAMPLE 40

A treatment such as that described in Example 9 wherein the patient is diagnosed with metastatic or non-metastatic kidney cancer.

EXAMPLE 41

A treatment such as that described in Example 9 wherein the patient is diagnosed with metastatic or non-metastatic livsr cancer.

EXAMPLE 42

A treatment such as that described in Example 9 wherein the patient is diagnosed with metastatic or non-metastatic lung cancer (small celi and/or non-small celi).

EXAMPLE 43

A treacment such as that described in Example 9 wherein

-120the patient is diagnosed vvith metastatic or non-metastatic malignant peritoneal effusion.

EXAMPLE 44

A treatment such as that described in Example 9 vvherein the patient is diagnosed vvith metastatic or non-metastatic malignant pleural effusion.

EXĀMPLE 45

A treatment such as that described in Example 9 vvherein the patient is diagnosed vvith metastatic or non-metastatic melanoma.

EXAMPLE 46

A treatment such as that described in Example 9 vvherein the patient is diagnosed vvith metastatic or non-metastatic mesothelioma.

EXAMPLE 47

A treatment such as that described in Example 9 vvherein the patient is diagnosed vvith metastatic or non-metastatic multiple myeloma.

EXAMPLE 48

A treatment such as that described in Example 9 vvherein the patient is diagnosed vvith metastatic or non-metastatic neuroblastoma.

EXAMPLE 49

A treatment such as that described in Example 9 vvherein the patient is diagnosed vvith metastatic or non-metastatic non-Hodgkin's lymphoma.

EXAMPLE 50

-121A treatment such as that described in Example 9 vvherein che patient is diagnosed vvith metastatic or non-metastatic osteosarcoma.

EXAMPLE 51

A treatment such as that described in Example 9 vvherein the patient is diagnosed vvith metastatic or non-metastatic ovarian cancer (and/or germ celi ovarian cancer).

A treatment such as the patient is diagnosed pancreatic cancer.

A treatment such as the patient is diagnosed 15 penis cancer.

A treatment such as the patient is diagnosed retinoblastoma.

A treatment such as the patient is diagnosed skin cancer.

A treatment such as the patient is diagnosed soft-tissue sarcoma.

EXAMPLE 52 that described in Example 9 vvherein vvith metastatic or non-metastatic

EXAMPLE 53 that described in Example 9 vvherein vvith metastatic or ncn-metastatic

EXAMPLE 54 that described in Example 9 vvherein vvith metastatic cr non-metastatic

EXAMPLE 55 that described in Example 9 vvherein vvith metastatic or non-metastatic

EXAMPLE 56

Chat described in Example 9 vvherein vvith metastatic or non-metastatic

-122EXAMPLE 57

Α treatment such as that described in Example 9 vvherein the patient is diagnosed vvith metastatic or non-metastatic squamous celi carcinoma.

EXAMPLE 58

A treatment such as that described in Example 9 vvherein the patient is diagnosed vvith metastatic or non-metastatic stomach cancer.

EXAMPLE 59

A treatment such as that described in Example 9 vvherein the patient is diagnosed vvith metastatic or non-metastatic testicular cancer.

EXAMPLE 60

A treatment such as that described in Example 9 vvherein the patient is diagnosed vvith metastatic or non-metastatic thyroid cancer.

EXAMPLE 61

A treatment such as that described in Example 9 vvherein the patient is diagnosed vvith metastatic or non-metastatic trophoblastic neoplasm.

EXAMPLE 62

A treatment such as that described in Example 9 vvherein the patient is diagnosed vvith metastatic or non-metastatic uterine cancer.

EXAMPLE 63

A treatment such as that described in Example 9 vvherein the patient is diagnosed vvith metastatic or non-metastatic vaginai cancer.

-123EXAMPLE 64

A treatment such as that described in Example 9 vvherein the patient is diagnosed vvith metastatic or non-metastatic cancer of the vulva.

EXAMPLE 65

A treatment such as that described in Example 9 vvherein the patient is diagnosed vvith metastatic or non-metastatic

Wilm's tumor.

The invention being thus described, it vvill be obvious 10 that the same may be varied in many ways. Such variations are not to be regarded as a departure from the spirit and scope of the invention and ali such modification are intended to be included vvithin the scope of the follovving claims.

1. Use of NAALADase inhibitor for treating cancer in an animai suffering from a cancer.

2. The use of claim 1, wherein the NAALADase inhibitor is selected from the group consisting of: a glutamatederived hydroxyphosphinyl derivative compound; an acidic peptide analog; a conformationally restricted glutamate mimic; and mixtures thereof.

3. The use of claim 2, wherein the NAALADase inhibitor is a glutamate-derived hydroxyphosphinyl derivative compound.

4. The use of claim 1, wherein the NAALADase inhibitor is used in combination with an additional therapeutic aģent selected from the group consisting of: therapeutic hormones, chemotherapeutic hormones, anti-angiogenesis aģents, radiolabelled compounds, and mixtures thereof.

5. The use of claim 1, wherein the cancer is selected from the group consisting of: ACTH-producing tumors, acute lymphocytic leukemia, acute nonlymphocytic leukemia, cancer of the adrenal cortex, bladder cancer, brain cancer, breast cancer, cervical cancer, chronic lymphocytic leukemia, chronic myelocytic leukemia, colorectal cancer, cutaneous T-cell lymphoma, endometrial cancer, esophageal cancer, Ewing's sarcoma, gallbladder cancer, hairy celi leukemia, head & neck cancer, Hodgkin's lymphoma, Kaposi's sarcoma, kidney cancer, liver cancer, lung cancer, lung cancer (small and/or non-small celi), malignant effusion, malignant pleural mesothelioma, multiple myeloma,

Hodgkin's lymphoma, osteosarcoma, ovary cancer, ovary (germ celi) cancer, pancreatic cancer, penis cancer, prostate peritoneal melanoma, effusion, neuroblastoma, non2 cancer, retinoblastoma, skin cancer, soft tissue sarcoma, squamous celi carcinomas, stomach cancer, testicular cancer, thyroid cancer, trophoblastic neoplasms, cancer of the uterus, vaginai cancer, cancer of the vulva, and Wilm's tumor.

6. The use of claim 1, vvherein the cancer is prostatic adenocarcinoma.

7. The use of claim 1, vvherein the cancer is selected from the group consisting of: brain cancer, cancer of the adrenal cortex, kidney cancer, and testicular cancer.

8. The use of claim 1, vvherein the NAALADase inhibitor comprises a compound having the follovving formula:

R2

Rl

COOH

Formula I, vvherein r is hydrogen, Cj.-Cg straight or branched chain alkyl, C₂-C₉ straight or branched chain alkenyl group, C₃-C₈ cycloalkyl, C₅-C_? cycloalkenyl, or Ar₁;

X is CH₂, 0, or NR_X, vvhere R₁ is defined above; and R₂ is C^-Cg straight or branched chain alkyl, C₂-C₉ straight or branched chain alkenyl group, C₃-C₃cycloalkyl, C₅-C₇ cycloalkenyl, or Ar_lZ vvherein said alkyl, alkenyl, cycloalkyl, cycloalkenyl or aryl· group may be optionally substituted vvith carboxylic acid, vvherein said aikyl, alkenyl, cycloalkyl, cycloalkenyl or aryl groups may be optionally substituted vvith C₃-C₃ cycloalkyl, C₃ or C₅ cycloalkyl, C₅-C₇ cycloalkenyl, C₁-C₄ alkyl, C₁-C₄ alkenyl, halo, hydroxy, carboxy, nitro, trifluoromethyl, C₁-C_g straight or branched chain alkyl or alkenyl, C^-C^ alkoxy, C_x-C₄ alkenyloxy, phenoxy, benzyloxy, amino, or Ar_v and vvhere Ar_x is selected from the group consisting of l-naphthyl, 2-naphthyl, 2-indolyl, 3-indolyl, 4-indolyl, 2-furyl, 3-furyl, tetrahydrofuranyl, 2-thienyl, 3-thienyl, 4-thienyl, 2-, 3-, or 4-pyridyl, or phenyl, having one to five substituents vvhich are independently selected from the group consisting of hydrogen, halo, hydroxy, carboxy, nitro, trifluoromethyl, C^-Cg straight or branched alkyl or alkenyl, C -C₄ alkoxy or C_x-C₄ alkenyloxy, phenoxy, benzyloxy, and amino; or pharmaceutically acceptable salts, hydrates, or mixtures thereof.

9. The use of claim 8, vvherein R_x and R₂ are straight or branched aliphatic groups or carbocyclic groups and X is ch₂.

10. The use of claim 9, vvherein the NAALADase inhibitor is selected from the group consisting of:

2-[[methylhydroxyphosphinyl]methyl]pentanedioic acid;

2-[[ethylhydroxyphosphinyl]methyl]pentanedioic acid;

2-[[propylhydroxyphosphinyl]methyl]pentanedioic acid;

2-[[butylhydroxyphosphinyl]methyl]pentanedioic acid;

2-[[cyclohexylhydroxyphosphinyl]methyl]pentanedioic acid;

- [ [(cyclohexyl)methylhydroxyphosphinyl]methyl] pentanedioic acid;

2-[[phenylhydroxyphosphinyl]methyl]pentanedioic acid;

2-[[benzylhydroxyphosphinyl]methyl]pentanedioic acid;

2- [ [phenylethylhydroxyphosphinyl]methyl]pentanedioic acid; 2-[[phenylpropylhydroxyphosphinyl]methyl]pentanedioic acid;

2-[[phenylbutylhydroxyphosphinyl]methyl]pentanedioic acid;

-[[(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;

2-[[(methoxybenzyl)hydroxyphosphinyl]methyl]pentanedioic acid;

2-[[(2,3,4 -trimethoxyphenyl)hydroxyphosphinyl]methyl] pentanedioic acid;

2-[[(l-naphthyl)hydroxyphosphinyl]methyl]pentanedioic acid;

2-[[(2-naphthyl)hydroxyphosphinyl]methyl]pentanedioic acid; 2-[[(l-naphthyl)methylhydroxyphosphinyl]methyl] pentanedioic acid;

2-[[(2-naphthyl)methylhydroxyphosphinyl]methyl] pentanedioic acid;

2-[[(l-naphthyl)ethylhydroxyphosphinyl]methyl]pentanedioic acid;

2-[[(2-naphthyl)ethylhydroxyphosphinyl]methyl]pentanedioic acid;

2-[[(l-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;

-[[(phenylprop-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 acid;

2-[[(4-fluorophenyl)hydroxyphosphinyl]methyl]pentanedioic acid;

2-(phosphonomethyl)pentanedioic acid;

2- [[(3-trifluoromethylbenzyl)hydroxyphosphinyl]methyl] pentanedioic acid;

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-phenylpropanoic acid; 3-(phenylbutylhydroxyphosphinyl)-2-phenylpropanoic acid; 3-((2,3,4-trimethoxyphenyl)-3-hydroxyphosphinyl)-2phenylpropanoic acid;

3-((l-naphthyl)hydroxyphosphinyl)-2-phenylpropanoic acid; 3-((2-naphthyl)hydroxyphosphinyl)-2-phenylpropanoic acid; 3-((l-naphthyl)-methylhydroxyphosphinyl)-2-phenylpropanoic acid;

3-((2-naphthyl)ethylhydroxyphosphinyl)-2-phenylpropanoic acid;

3-((l-naphthyl)ethylhydroxyphosphinyl)-2-phenylpropanoic acid;

3-((2-naphthyl)ethylhydroxyphosphinyl)-2-phenylpropanoic acid;

3-((l-naphthyl)propylhydroxyphosphinyl)-2-phenylpropanoic acid;

3-((2-naphthyl)propylhydroxyphosphinyl)-2-phenylpropanoic acid;

3-((l-naphthyl)butylhydroxyphosphinyl)-2-phenylpropanoic acid;

3-((2-naphthyl)butylhydroxyphosphinyl)-2-phenylpropanoic acid;

3-(phenylprop-2-enylhydroxyphosphinyl)-2-phenylpropanoic acid;

2-[(benzylhydroxyphosphinyl)methyl] pentanedioic acid;

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]octanedioic acid;

2-[(methylhydroxyphosphinyl)methyl]nonanedioic acid;

2-[(benzylhydroxyphosphinyl)methyl]nonanedioic acid;

2-[(methylhydroxyphosphinyl)methyl]decanedioic acid;

2- [(benzylhydroxyphosphinyl)methyl]decanedioic acid;

3- (benzylhydroxyphosphinyl)-2-methylpropanoic acid;

3-(benzylhydroxyphosphinyl)-2-ethylpropanoic acid;

3-(benzylhydroxyphosphinyl)-2-propylpropanoic acid;

3-(benzylhydroxyphosphinyl)-2-butylpropanoic acid;

3-(benzylhydroxyphosphinyl)-2-cyclohexylpropanoic acid;

3-(benzylhydroxyphosphinyl)-2-(cyclohexyl)methylpropanoic acid;

3-(benzylhydroxyphosphinyl)-2-phenylpropanoic acid;

3-(benzylhydroxyphosphinyl)-2-benzylpropanoic acid;

3-(benzylhydroxyphosphinyl)-2-phenylethylpropanoic acid;

3-(benzylhydroxyphosphinyl)-2-phenylpropylpropanoic acid; 3-(benzylhydroxyphosphinyl)-2-phenylbutylpropanoic acid;

3-(benzylhydroxyphosphinyl)-2-(2,3,4 -trimethoxyphenyl) propanoic acid;

3-(benzylhydroxyphosphinyl)-2-(1-naphthyl)propanoic acid;

-(benzylhydroxyphosphinyl)-2 -(2 -naphthyl)propanoic acid; 3-(benzylhydroxyphosphinyl)-2-(l-naphthyl)methylpropanoic acid;

3-(benzylhydroxyphosphinyl)-2-(2-naphthyl)methylpropanoic acid;

3-(benzylhydroxyphosphinyl)-2-(l-naphthyl)ethylpropanoic acid;

3-(benzylhydroxyphosphinyl)-2-(2-naphthyl)ethylpropanoic acid;

3-(benzylhydroxyphosphinyl)-2-(l-naphthyl)propylpropanoic acid;

3-(benzylhydroxyphosphinyl)-2-(2-naph.th.yl) propylpropanoic acid;

3-(benzylhydroxyphosphinyl)-2-(l-naphthyl)butylpropanoic acid;

3-(benzylhydroxyphosphinyl)-2-(2-naphthyl)butylpropanoic acid;

3-(benzylhydroxyphosphinyl)-2-phenylprop-2-enylpropanoic acid;

2-[[(2-pyridyl)methylhydroxyphosphinyl]methyl]pentanedioic acid;

- [ [(3-pyridyl)methylhydroxyphosphinyl]methyl]pentanedioic acid;

2-[[(4-pyridyl)methylhydroxyphosphinyl]methyl]pentanedioic acid;

-[[(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)propylhydroxyphosphinyl]methyl] pentanedioic acid;

2-[[(2-indolyl)methylhydroxyphosphinyl]methyl]pentanedioic acid;

-[[(3 -indoly1)methylhydroxyphosphinyl]methyl] pentanedioic acid;

2-[[(4-indolyl)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;

-[[(3 -thienyl)ethylhydroxyphosphinyl]methyl]pentanedioic acid;

2-[[(3-thienyl)propylhydroxyphosphinyl]methyl] pentanedioic acid;

3-[(2-pyridyl)methylhydroxyphosphinyl]-2-phenylpropanoic acid;

3-[(3-pyridyl)methylhydroxyphosphinyl]-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]-2phenylpropanoic acid;

3-[(tetrahydrofuranyl)ethylhydroxyphosphinyl]-2-phenyl propanoic acid;

3-[(tetrahydrofuranyl)propylhydroxyphosphinyl)-2-phenyl propanoic 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-phenylpropanoic acid;

3-(benzylhydroxyphosphinyl)-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-(tetrahydrofuranyl)methyl propanoic acid;

3-(benzylhydroxyphosphinyl)-2-(tetrahydrofuranyl)ethyl propanoic acid;

3-(benzylhydroxyphosphinyl)-2-(tetrahydrofuranyl)propyl propanoic 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)ethylpropanoic 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;

and a pharmaceutically acceptable salt, hydrate, or a mixture thereof.

11. The use of claim 9, vvherein the NAALADase inhibitor is selected from the group consisting of:

2-[(benzylhydroxyphosphinyl)methyl]pentanedioic acid;

2-[(phenylhydroxyphosphinyl)methyl]pentanedioic acid;

-[[((hydroxy)phenylmethyl)hydroxyphosphinyl]methyl] pentanedioic acid;

2-[(butylhydroxyphosphinyl)methyl]pentanedioic acid;

2-[[(3-methylbenzyl)hydroxyphosphinyl]methyl]pentanedioic acid;

2-[(3-phenylpropylhydroxyphosphinyl)methyl]pentanedioic acid;

- [ [(4 -fluorophenyl)hydroxyphosphinyl]methyl]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;

-[[(4-methoxybenzyl)hydroxyphosphinyl]methyl]pentanedioic acid;

2-(phosphonomethyl)pentanedioic acid;

2- [ [3 - trif lu.oromethylben.zyl) hydroxyphosphinyl ] methyl] pentanedioic acid;

2-[[2-fluorobenzyl)hydroxyphosphinyl]methyl]pentanedioic acid;

- [ [ (pentafluorobenzyl)hydroxyphosphinyl]methyl] pentanedioic acid; and a pharmaceutically acceptable salt, hydrate, or a mixture thereof.

12. The use of claim 8, wherein R and R₂ are straight or branched aliphatic groups or carbocyclic groups and X is oxygen.

13. The use of claim 12, wherein the NAALADase inhibitor is selected from the group consisting of:

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;

- [ [(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-[[(2,3,4-trimethoxyphenyl)hydroxyphosphinyl]oxy] pentanedioic acid;

2-[[(l-naphthyl)hydroxyphosphinyl]oxy]pentanedioic acid;

- [ [ (2-naphthyl)hydroxyphosphinyl]oxy]pentanedioic acid;

2-[[(l-naphthyl)methylhydroxyphosphinyl]oxy]pentanedioic acid;

2-[[(2-naphthyl)methylhydroxyphosphinyl]oxy]pentanedioic acid;

2-[[(l-naphthyl)ethylhydroxyphosphinyl]oxy]pentanedioic acid;

2-[[(2-naphthyl)ethylhydroxyphosphinyl]oxy]pentanedioic acid;

2-[[(l-naphthyl)propylhydroxyphosphinyl]oxy]pentanedioic acid;

-[[(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;

-[[(4-fluorophenyl)hydroxyphosphinyl]oxy]pentanedioic acid;

2-[[(2-fluorobenzyl)hydroxyphosphinyl]oxy]pentanedioic acid;

2-(phosphono)oxy]pentanedioic acid;

2-[[(3-trifluoromethylbenzyl)hydroxyphosphinyl]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-phenylethanoic acid;

2-[[cyclohexylhydroxyphosphinyl]oxy]-2-phenylethanoic acid; 2-[[(cyclohexyl)methylhydroxyphosphinyl]oxy]-2phenylethanoic acid;

2-[[phenylhydroxyphosphinyl]oxy]-2-phenylethanoic acid;

2-[[benzylhydroxyphosphinyl]oxy]-2-phenylethanoic acid;

2-[[phenylethylhydroxyphosphinyl]oxy]-2-phenylethanoic acid;

2-[[phenylpropylhydroxyphosphinyl]oxy]-2-phenylethanoic acid;

2-[[phenylbutylhydroxyphosphinyl]oxy]-2-phenylethanoic acid;

-[[(2,3,4-trimethoxyphenyl)-3-hydroxyphosphinyl]oxy]-2 phenylethanoic acid;

2-[[(l-naphthyl)hydroxyphosphinylloxy]-2-phenylethanoic acid;

2-[[(2-naphthyl)hydroxyphosphinyl]oxy]-2-phenylethanoic acid;

2-[[(l-naphthyl)methylhydroxyphosphinyl]oxy]-2phenylethanoic acid;

2-[[(2-naphthyl)methylhydroxyphosphinyl]oxy]-2phenylethanoic acid;

2-[[(l-naphthyl)ethylhydroxyphosphinyl]oxy]-2phenylethanoic acid;

-[[(2-naphthyl)ethylhydroxyphosphinyl]oxy]- 2 phenylethanoic acid;

2-[[(l-naphthy)propylhydroxyphosphinyl]oxy]-2phenylethanoic acid;

2-[[(2-naphthyl)propylhydroxyphosphinyl]oxy]-2phenylethanoic acid;

- [ [(l-naphthyl,butylhydroxyphosphinyl]oxy]-2phenylethanoic acid;

2-[[(2-naphthyl)butylhydroxyphosphinyl]oxy]-2phenylethanoic acid;

2-[[phenylprop-2-enylhydroxyphosphinyl]oxy]-2phenylethanoic acid;

-[(methylhydroxyphosphinyl)oxy]hexanedioic acid;

2-[(benzylhydroxyphosphinyl)oxy]hexanedioic acid;

2-[(methylhydroxyphosphinyl)oxy]heptanedioic acid;

2-[(benzylhydroxyphosphinyl)oxy]heptanedioic acid;

2-[(methylhydroxyphosphinyl)oxy]octanedioic acid;

2-[(benzylhydroxyphosphinyl)oxy]octanedioic acid;

2-[(methylhydroxyphosphinyl)oxy]nonanedioic acid;

2-[(benzylhydroxyphosphinyl)oxy]nonanedioic acid;

2-[(methylhydroxyphosphinyl)oxy]decanedioic acid;

2-[(benzylhydroxyphosphinyl)oxy]decanedioic acid;

2-[ [benzylhydroxyphosphinyl]oxy]-2-methylethanoic acid;

2- [ [benzylhydroxyph.osph.inyl] oxy] -2-ethylethanoic acid;

2- [ [benzylhydroxyphosphinyl]oxy]-2-propylethanoic acid;

2-[[benzylhydroxyphosphinyl]oxy]-2-butylethanoic acid;

2-[[benzylhydroxyphosphinyl]oxy]-2-cyclohexylethanoic acid; 2-[[benzylhydroxyphosphinyl]oxy]-2-(cyclohexyl) methylethanoic acid;

2-[[benzylhydroxyphosphinyl]oxy]-2-phenylethanoic acid;

2-[[benzylhydroxyphosphinyl]oxy]-2-benzylethanoic acid;

2-[[benzylhydroxyphosphinyl]oxy]-2-phenylethylethanoic acid;

2-[[benzylhydroxyphosphinyl]oxy]-2-phenylpropylethanoic acid;

2-[[benzylhydroxyphosphinyl]oxy]-2-phenylbutylethanoic acid;

-[ [benzylhydroxyphosphinyl]oxy]-2 -(2,3,4trimethoxyphenyl)ethanoic acid;

2-[[benzylhydroxyphosphinyl]oxy]-2-(l-naphthyl)ethanoic acid;

2-[[benzylhydroxyphosphinyl]oxy]-2-(2-naphthyl)ethanoic acid;

2-[[benzylhydroxyphosphinyl]oxy]-2-(l-naphthyl) methylethanoic acid;

2-[[benzylhydroxyphosphinyl]oxy]-2-(2-naphthyl) methylethanoic acid;

2-[[benzylhydroxyphosphinyl]oxy]-2-(l-naphthyl) ethylethanoic acid;

2-[[benzylhydroxyphosphinyl]oxy]-2-(2-naphthyl) ethylethanoic acid;

2-[[benzylhydroxyphosphinyl]oxy]-2-(l-naphthyl) propylethanoic acid;

2-[[benzylhydroxyphosphinyl]oxy]-2-(2-naphthyl) propylethanoic acid;

2-[[benzylhydroxyphosphinyl]oxy]-2-(l-naphthyl) butylethanoic acid;

2-[[benzylhydroxyphosphinyl]oxy]-2-(2-naphthyl) butylethanoic acid;

2-[[benzylhydroxyphosphinyl]oxy]-2-phenylprop-2enylethanoic acid;

2-[[(2-pyridyl)methylhydroxyphosphinyl]oxy]pentanedioic acid;

- [ [(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)propylhydroxyphosphinyl]oxy] pentanedioic acid;

2-[[(2-indolyl)methylhydroxyphosphinyl]oxy]pentanedioic acid;

2-[[(3-indolyl)methylhydroxyphosphinyl]oxy]pentanedioic acid;

— [ [(4-indolyl)methylhydroxyphosphinyl]oxy]pentanedioic acid;

2-[[(3-indolyl)ethylhydroxyphosphinyl]oxy]pentanedioic acid;

- [ [(3-indolyl)propylhydroxyphosphinyl]oxy]pentanedioic acid;

2-[[(2-thienyl)methylhydroxyphosphinyl]oxy]pentanedioic acid ;

- [((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;

-[[(2-pyridyl)methylhydroxyphosphinyl]oxy]- 2 phenylethanoic acid;

2-[[(3-pyridyl)methylhydroxyphosphinyl]oxy]-2phenylethanoic acid;

2-[[(4-pyridyl)methylhydroxyphosphinyl]oxy]-2phen.ylethan.oic acid;

2-[[(3-pyridyl)ethylhydroxyphosphinyl]oxy]-2-phenylethanoic acid;

-[[(3-pyridyl)propylhydroxyphosphinyl]oxy]-2 phenylethanoic acid;

2-[[(tetrahydrofuranyl)methylhydroxyphosphinyl]oxy]-2phenylethanoic acid;

2-[[(tetrahydrofuranyl)ethylhydroxyphosphinyl]oxy]-2phenylethanoic acid;

2-[[(tetrahydrofuranyl)propylhydroxyphosphinyl]oxy]-2phenylethanoic acid;

2-[[(2-indolyl)methylhydroxyphosphinyl]oxy]-2-phenyl ethanoic acid;

2-[[(3-indolyl)methylhydroxyphosphinyl]oxyļ-2-phenyl ethanoic acid;

2-[[(4-indolyl)methylhydroxyphosphinyl]oxy]-2-phenyl ethanoic acid;

2-[[(3-indolyl)ethylhydroxyphosphinyl]oxy]-2-phenyl ethanoic acid;

2-[[(3-indolyl)propylhydroxyphosphinyl]oxy]-2-phenyl ethanoic acid;

2-[((2-thienyl)methylhydroxyphosphinyl]oxy]-2-phenyl ethanoic acid;

2-[[(3-thienyl)methylhydroxyphosphinyl]oxy]-2-phenyl ethanoic acid;

2-[[(4-thienyl)methylhydroxyphosphinyl]oxy]-2-phenyl ethanoic acid;

2-[[(3-thienyl)ethylhydroxyphosphinyl]oxy]-2-phenyl ethanoic acid;

-[[(3-thienyl)propylhydroxyphosphinyl]oxy]-2-phenyl ethanoic acid;

2-[[benzylhydroxyphosphinyl]oxy]-2-(2-pyridyl)methyl ethanoic acid;

2-[[benzylhydroxyphosphinyl]oxy]-2-(3-pyridyl)methyl ethanoic acid;

2-[[benzylhydroxyphosphinyl]oxy]-2-(4-pyridyl)methyl ethanoic acid;

2-[[benzylhydroxyphosphinyl]oxy]-2-(3-pyridyl)ethyl ethanoic acid;

2-[[benzylhydroxyphosphinyl]oxy]-2-(3-pyridyl)propyl ethanoic acid;

2-[[benzylhydroxyphosphinyl]oxy]-2-(tetrahydrafuranyl) methylethanoic acid;

2-[[benzylhydroxyphosphinyl]oxy]-2-(tetrahydrafuranyl) ethylethanoic acid;

2-[[benzylhydroxyphosphinyl]oxy]-2-(tetrahydrafuranyl) propylethanoic acid;

2-[[benzylhydroxyphosphinyl]oxy]-2-(2-indolyl)methyl ethanoic acid;

2-[[benzylhydroxyphosphinyl]oxy]-2-(3-ndolyl)methyl ethanoic acid;

2-[[benzylhydroxyphosphinyl]oxy]-2-(4-indolyl)methyl ethanoic acid;

2-[[benzylhydroxyphosphinyl]oxy]-2-(3-indolyl)ethyl ethanoic acid;

-[[benzylhydroxyphosphinyl]oxy]-2 -(3 -indolyl)propyl ethanoic acid;

2-[[benzylhydroxyphosphinyl]oxy]-2-(2-thienyl)methyl ethanoic acid;

2-[[benzylhydroxyphosphinyl]oxy]-2-(3 -thienyl)methyl ethanoic acid;

2-[[benzylhydroxyphosphinyl]oxy]-2-(4-thienyl)methyl ethanoic acid;

2-[[benzylhydroxyphosphinyl]oxy]-2-(3-thienyl)ethyl ethanoic acid;

2-[[benzylhydroxyphosphinyl]oxy]-2-(3-thienyl)propyl ethanoic acid;

and a pharmaceutically acceptable salt, hydrate, or a mixture thereof.

14. The use of claim 12, vvherein the NAALADase inhibitor is selected from the group consisting of:

2-[(benzylhydroxyphosphinyl)oxy]pentanedioic acid;

2-[(phenylhydroxyphosphinyl)oxy]pentanedioic acid;

-[[((hydroxy)phenylmethyl)hydroxyphosphinyl]oxy] pentanedioic acid;

2-[(butylhydroxyphosphinyl)oxy]pentanedioic acid;

2-[[(3-methylbenzyl)hydroxyphosphinyl]oxy]pentanedioic acid;

2-[(3-phenylpropylhydroxyphosphinyl)oxy]pentanedioic acid; 2-[[(4-fluorophenyl)hydroxyphosphinyl]oxy]pentanedioic acid;

2-[(methylhydroxyphosphinyl)oxy]pentanedioic acid;

2-[(phenylethylhydroxyphosphinyl)oxy]pentanedioic acid;

- [ [(4-methylbenzyl)hydroxyphosphinyl]oxy]pentanedioic acid;

2- [ [(4-fluorobenzyl)hydroxyphosphinyl]oxy]pentanedioic acid;

2-[[(4-methoxybenzyl)hydroxyphosphinyl]oxy]pentanedioic acid;

2-[(phosphono)oxy]pentanedioic acid;

2-[[(3-trifluoromethylbenzyl)hydroxyphosphinyl]oxy] pentanedioic acid;

2-[[(2-fluorobenzyl)hydroxyphosphinyl]oxy]pentanedioic acid;

-[[(pentafluorobenzyl)hydroxyphosphinyl]oxy]pentanedioic acid; and a pharmaceutically acceptable salt, hydrate, or a mixture thereof.

15. The use of claim 8, wherein R_x and R₂ are straight or branched aliphatic groups or carbocyclic groups and X is NR^

16. The use of claim 15, wherein the NAALADase inhibitor is selected from the group consisting of:

2-[[methylhydroxyphosphinyl]amino]pentanedioic acid;

2-[[ethylhydroxyphosphinyl]amino]pentanedioic acid;

2-[[propylhydroxyphosphinyl]amino]pentanedioic acid;

2-[[butylhydroxyphosphinyl]amino]pentanedioic acid;

2-[[cyclohexylhydroxyphosphinyl]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]pentanedioic acid;

2-[[(4-methylbenzyl)hydroxyphosphinyl]amino]pentanedioic acid;

2-[[(4-fluorobenzyl)hydroxyphosphinyl]amino]pentanedioic acid;

-[[(2-fluorobenzyl)hydroxyphosphinyl]amino]pentanedioic acid;

2-[[(pentafluorobenzyl)hydroxyphosphinyl]amino] pentanedioic acid;

2-[[methoxybenzyl)hydroxyphosphinyl]amino]pentanedioic acid;

2-[[(2, 3, 4-trimethoxyphenyl)hydroxyphosphinyl]amino] pentanedioic acid;

2-[[l-naphthyl)hydroxyphosphinyl]amino]pentanedioic acid;

2-[[(2-naphthyl)hydroxyphosphinyl]amino]pentanedioic acid; 2-[[(l-naphthyl)methylhydroxyphosphinyl]amino]pentanedioic acid;

2-[[(2-naphthyl)methylhydroxyphosphinyl]amino]pentanedioic acid;

2-[[(l-naphthyl)ethylhydroxyphosphinyl]amino]pentanedioic acid;

2-[[(2-naphthyl)ethylhydroxyphosphinyl]amino]pentanedioic acid;

2-[[(l-naphthyl)propylhydroxyphosphinyl]amino]pentanedioic acid;

2-[[(2-naphthyl)propylhydroxyphosphinyl]amino]pentanedioic acid;

2-[[(l-naphthyl)butylhydroxyphosphinyl]amino]pentanedioic acid;

2-[[(2-naphthyl)butylhydroxyphosphinyl]amino]pentanedioic acid;

-[[(phenylprop-2-enyl)hydroxyphosphinyl]amino] pentanedioic acid;

2-[[benzylhydroxyphosphinyl]amino]pentanedioic acid;

2-[((2-fluorobenzyl)hydroxyphosphinyl]amino]-2pentanedioic 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;

- [[(3-trifluoromethylbenzyl)hydroxyphosphinyl]amino] pentanedioic acid;

2-[[methylhydroxyphosphinyl]amino]-2-phenylethanoic acid; 2-[[ethylhydroxyphosphinyl]amino]-2-phenylethanoic acid;

2-[[propylhydroxyphosphinyl]amino]-2-phenylethanoic acid; 2-[[butylhydroxyphosphinyl]amino]-2-phenylethanoic acid;

2-[[cyclohexylhydroxyphosphinyl]amino]-2-phenylethanoic acid;

2-[[(cyclohexyl)methylhydroxyphosphinyl]amino]-2-phenyl ethanoic acid;

2-[[phenylhydroxyphosphinyl]amino] -2-phenylethanoic acid; 2-[[benzylhydroxyphosphinyl]amino]-2-phenylethanoic acid; 2-[[phenylethylhydroxyphosphinyl]amino]-2-phenylethanoic acid;

2-[[phenylpropylhydroxyphosphinyl]amino]-2-phenylethanoic acid;

2-[[phenylbutylhydroxyphosphinyl]amino]-2-phenylethanoic acid;

2- [ [ (2,3 ,4-trimethoxyphenyl)-3-hydroxyphosphinyl]amino]-2phenylethanoic acid;

-[[(l-naphthyl)hydroxyphosphinyl]amino]-2-phenylethanoic acid;

- [ [(2-naphthyl)hydroxyphosphinyl]amino]-2-phenylethanoic acid;

2-[[(l-naphthyl)methylhydroxyphosphinyl]amino]-2-phenyl ethanoic acid;

2-[[(2-naphthyl)methylhydroxyphosphinyl]amino]-2-phenyl ethanoic acid;

2-[[(l-naphthyl)ethylhydroxyphosphinyl]amino]-2-phenyl ethanoic acid;

2-[[(2-naphthyl)ethylhydroxyphosphinyl]amino]-2-phenyl ethanoic acid;

2- [ [(l-naphthyl)propylhydroxyphosphinyl]amino]-2-phenyl ethanoic acid;

2-[[(2-naphthyl)propylhydroxyphosphinyl]amino]-2-phenyl ethanoic acid;

-[[(l-naphthyl)butylhydroxyphosphinyl]amino]-2-phenyl ethanoic acid;

- [ [(2-naphthyl)butylhydroxyphosphinyl]amino]-2phenylethanoic acid;

2-[[phenylprop-2-enylhydroxyphosphinyl]amino]-2phenylethanoic acid;

2-[[benzylhydroxyphosphinyl]amino]-2-methylethanoic acid; 2-[[benzylhydroxyphosphinyl]amino]-2-ethylethanoic acid; 2-[[benzylhydroxyphosphinyl]amino]-2-propylethanoic acid; 2-[[benzylhydroxyphosphinyl]amino]-2-butylethanoic acid; 2- [ [benzylhydroxyphosphinyl]amino]-2-cyclohexylethanoic acid;

2-[[benzylhydroxyphosphinyl]amino]-2-(cyclohexyl)methyl ethanoic acid;

2-[[benzylhydroxyphosphinyl]amino]-2-phenylethanoic acid; 2-[[benzylhydroxyphosphinyl]amino]-2-benzylethanoic acid; 2-[[benzylhydroxyphosphinyl]amino]-2-phenylethylethanoic acid;

2-[[benzylhydroxyphosphinyl]amino]-2-phenylpropylethanoic acid;

2-[[benzylhydroxyphosphinyl]amino]-2-phenylbutylethanoic acid;

-[[benzylhydroxyphosphinyl]amino] -2 -(2,3,4trimethoxyphenyl)ethanoic acid;

2-[[benzylhydroxyphosphinyl]amino]-2-(l-naphthyl)ethanoic acid;

2-[[benzylhydroxyphosphinyl]amino]-2-(2-naphthyl)ethanoic acid;

2-[[benzylhydroxyphosphinyl]amino]-2-(l-naphthyl)methyl ethanoic acid;

2-[[benzylhydroxyphosphinyl]amino]-2-(2-naphthyl)methyl ethanoic acid;

2-[[benzylhydroxyphosphinyl]amino]-2-(l-naphthyl)ethyl ethanoic acid;

2-[[benzylhydroxyphosphinyl]amino]-2-(2-naphthyl)ethyl ethanoic acid;

2-[[benzylhydroxyphosphinyl]amino]-2-(1-naphthyl)propyl ethanoic acid;

2-[[benzylhydroxyphosphinyl]amino]-2-(2-naphthyl)propyl ethanoic acid;

2-[[benzylhydroxyphosphinyl]amino]-2-(l-naphthyl)butyl ethanoic acid;

2-[[benzylhydroxyphosphinyl]amino]-2-(2-naphthyl)butyl ethanoic acid;

2-[[benzylhydroxyphosphinyl]amino]-2-phenolprop-2-enyl ethanoic 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]nonanedioic acid;

2-[(benzylhydroxyphosphinyl)amino]nonanedioic 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;

-[[(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;

-[[(tetrahydrofuranyl)ethylhydroxyphosphinyl]amino] pentanedioic acid;

3-[[(tetrahydrofuranyl)propylhydroxyphosphinyl]amino] pentanedioic acid;

- [ [(2-indolyl)methylhydroxyphosphinyl]amino]pentanedioic acid;

3-[[(3-indolyl) methylhydroxyphosphinyl]amino]pentanedioic acid;

3-t[(4-indolyl)methylhydroxyphosphinyl]amino]pentanedioic acid;

3-[[(3-indolyl)ethylhydroxyphosphinyl]amino]pentanedioic acid;

-[[(3 -indolyl)propylhydroxyphosphinyl]amino]pentanedioic acid;

3-[[(2-thienyl)methylhydroxyphosphinyl]amino]pentanedioic acid;

-[[(3-thienyl)methylhydroxyphosphinyl]amino]pentanedioic acid;

-[[(4-thienyl)methylhydroxyphosphinyl]amino]pentanedioic acid;

3- [ [(3-thienyl)ethylhydroxyphosphinyl]amino]pentanedioic acid;

3-[[(3-thienyl)propylhydroxyphosphinyl]amino]pentanedioic acid;

2-[[(2-pyridyl)methylhydroxyphosphinyl]amino]-2-phenyl ethanoic acid;

2-[[(3-pyridyl)methylhydroxyphosphinyl]amino]-2-phenyl ethanoic acid;

2-[[(4-pyridyl)methylhydroxyphosphinyl]amino]-2-phenyl ethanoic acid;

2-[[(3-pyridyl)ethylhydroxyphosphinyl]amino]-2-phenyl ethanoic acid;

2-[[(3-pyridyl)propylhydroxyphosphinyl]amino]-2-phenyl ethanoic acid;

2-[[(tetrahydrofuranyl)methylhydroxyphosphinyl]amino]-2phenylethanoic acid;

2-[[(tetrahydrofuranyl)ethylhydroxyphosphinyl]amino]-2phenylethanoic acid;

2-[[(tetrahydrofuranyl)propylhydroxyphosphinyl]amino]-2phenylethanoic acid;

2-[[(2-indolyl)methylhydroxyphosphinyl]amino]-2-phenyl ethanoic acid;

2-[[3-indolyl)methylhydroxyphosphinyl]amino]-2-phenyl ethanoic acid;

- [ [(4-indolyl)methylhydroxyphosphinyl]amino]-2-phenyl ethanoic acid;

2-[[(3-indolyl)ethylhydroxyphosphinyl]amino]-2-phenyl ethanoic acid;

2-[[(3-indolyl)propylhydroxyphosphinyl]amino]-2-phenyl ethanoic acid;

2-[[(2-thienyl)methylhydroxyphosphinyl]amino]-2-phenyl ethanoic acid;

2-[[(3-thieny)methylhydroxyphosphinyl]amino]-2-phenyl ethanoic acid;

2-[[(4-thienyl)methylhydroxyphosphinyl]amino]-2-phenyl ethanoic acid;

2-[[(3-thienyl)ethylhydroxyphosphinyl]amino]-2-phenyl ethanoic acid;

2-[[(3-thieny)propylhydroxyphosphinyl]amino]-2phenylethanoic acid;

2-[[benzylhydroxyphosphinyl]amino]-2-(2-pyridyl)methyl ethanoic acid;

2-[[benzylhydroxyphosphinyl]amino]-2-(3-pyridyl)methyl ethanoic acid;

2-[[benzylhydroxyphosphinyl]amino]-2-(4-pyridyl)methyl ethanoic acid;

2-[[benzylhydroxyphosphinyl]amino]-2-(3-pyridyl)ethyl ethanoic acid;

2-[[benzylhydroxyphosphinyl]amino]-2-(3-pyridyl)propyl ethanoic acid;

2-[[benzylhydroxyphosphinyl]amino]-2-(tetrahydrafuranyl) methylethanoic acid;

2-[[benzylhydroxyphosphinyl]amino]-2-(tetrahydrafuranyl) ethylethanoic acid;

2-[[benzylhydroxyphosphinyl]amino]-2-(tetrahydrafuranyl) propylethanoic acid;

2-[[benzylhydroxyphosphinyl]amino]-2-(2-indolyl)methyl ethanoic acid;

2-[[benzylhydroxyphosphinyl]amino]-2-(3 -indolyl)methyl ethanoic acid;

2-[[benzylhydroxyphosphinyl]amino]-2-(4-indolyl)methyl ethanoic acid;

2-[[benzylhydroxyphosphinyl]amino]-2-(3-indolyl)ethyl ethanoic acid;

2-[[benzylhydroxyphosphinyl]amino]-2-(3-indolyl)propyl ethanoic acid;

2-[[benzylhydroxyphosphinyl]amino]-2-(2-thienyl)methyl ethanoic acid;

2-[[benzylhydroxyphosphinyl]amino]-2-(3-thienyl)methyl ethanoic acid;

2-[[benzylhydroxyphosphinyl]amino]-2-(4 -thienyl)methyl ethanoic acid;

2-[[benzylhydroxyphosphinyl]amino]-2-(3-thienyl)ethyl ethanoic acid;

2-[[benzylhydroxyphosphinyl]amino]-2-(3-thienyl)propyl ethanoic acid; and a pharmaceutically acceptable salt, hydrate, or a mixture thereof.

17. The use of claim 15, vvherein the NAALADase inhibitor is selected from the group consisting of:

2-[(benzylhydroxyphosphinyl)amino]pentanedioic acid;

2-[(phenylhydroxyphosphinyl)amino]pentanedioic acid;

-[[((hydroxy)phenylmethyl)hydroxyphosphinyl]amino] pentanedioic acid;

2-[(butylhydroxyphosphinyl)amino]pentanedioic acid;

2-[[(3-methylbenzyl)hydroxyphosphinyl]amino]pentanedioic acid;

2-[(3-phenylpropylhydroxyphosphinyl)amino]pentanedioic acid;

-[[(4 -fluorophenyl)hydroxyphosphinyl] amino]pentanedioic acid;

2-[(methylhydroxyphosphinyl)amino]pentanedioic acid;

2-[(phenylethylhydroxyphosphinyl)amino]pentanedioic acid;

2-[[(4-methylbenzyl)hydroxyphosphinyl]amino]pentanedioic acid;

2-[[(4-fluorobenzyl)hydroxyphosphinyl]amino]pentanedioic acid;

-[[(4-methoxybenzyl)hydroxyphosphinyl]amino]pentanedioic acid;

2-[(phosphono)amino]pentanedioic acid;

2-[[(3-trifluoromethylbenzyl)hydroxyphosphinyl]amino] pentanedioic acid;

2-[[(2-fluorobenzyl)hydroxyphosphinyl]amino]pentanedioic acid;

2-[[(pentafluorobenzyl)hydroxyphosphinyl]amino] pentanedioic acid; and a pharmaceutically acceptable salt, hydrate, or a mixture thereof.

18. The use of claim 8, vvherein R_x or R₂ is heterocyclic and X is CH₂.

19. The use of claim 18, vvherein the NAALADase inhibitor is selected from the group consisting of:

2-[[(2-pyridyl)hydroxyphosphinyl]methyl]pentanedioic acid; 2-[[(3-pyridyl)hydroxyphosphinyl]methyl]pentanedioic acid; 2-[[(4-pyridyl)hydroxyphosphinyl]methyl]pentanedioic acid;

- [ [(tetrahydrofuranyl)hydroxyphosphinyl]methyl] pentanedioic acid;

2-[[(2-indolyl)hydroxyphosphinyl]methyl]pentanedioic acid; 2-[[(3-indolyl)hydroxyphosphinyl]methyl]pentanedioic acid; 2-[[(4-indolyl)hydroxyphosphinyl]methyl]pentanedioic acid;

2-[[(2-thienyl)hydroxyphosphinyl]methyl]pentanedioic acid; 2-[[(3-thienyl)hydroxyphosphinyl]methyl]pentanedioic acid;

2- [[(4-thienyl)hydroxyphosphinyl]methyl]pentanedioic acid;

- [ (2 -pyridyl) hydroxyphosphinyl ] - 2 -phenylpropanoic acid ·,

-[(3-pyridyl)hydroxyphosphinyl]-2-phenylpropanoic acid;

3- [(4-pyridyl)hydroxyphosphinyl]-2-phenylpropanoic acid;

3-[(tetrahydrofuranyl)hydroxyphosphinyl]-2-phenylpropanoic acid;

3-[(2-indolyl)hydroxyphosphinyl]-2-phenylpropanoic acid;

3-[(3-indolyl)hydroxyphosphinyl]-2-phenylpropanoic acid;

3-[(4-indolyl)hydroxyphosphinyl]-2-phenylpropanoic acid;

3-[(2-thienyl)hydroxyphosphinyl]-2-phenylpropanoic acid;

3-[(3-thienyl)hydroxyphosphinyl]-2-phenylpropanoic acid;

3-[(4-thienyl)hydroxyphosphinyl]-2-phenylpropanoic acid;

3-(benzylhydroxyphosphinyl)-2-(2-pyridyl)propanoic acid;

3-(benzylhydroxyphosphinyl)-2-(3-pyridyl)propanoic acid;

3-(benzylhydroxyphosphinyl)-2-(4-pyridyl)propanoic acid;

3-(benzylhydroxyphosphinyl)-2-(tetrahydrofuranyl)propanoic acid;

3-(benzylhydroxyphosphinyl)-2-(2-indolyl)propanoic acid;

3-(benzylhydroxyphosphinyl)-2-(3-indolyl)propanoic acid;

3-(benzylhydroxyphosphinyl)-2-(4-indolyl)propanoic acid;

3-(benzylhydroxyphosphinyl)-2-(2-thienyl)propanoic acid;

3-(benzylhydroxyphosphinyl)-2-(3-thienyl)propanoic acid;

3-(benzylhydroxyphosphinyl)-2-(4-thienyl)propanoic acid; and a pharmaceutically acceptable salt, hydrate, or a mixture thereof.

20. The use of claim 8, vvherein R_x or R₂ is heterocyclic and X is oxygen.

21. The use of claim 20, vvherein the NAALADase inhibitor is selected from the group consisting of:

2-[[(2-pyridyl)hydroxyphosphinyl]oxy]pentanedioic acid;

2-[[(3-pyridyl)hydroxyphosphinyl]oxylpentanedioic acid;

2-[[(4-pyridyl)hydroxyphosphinyl]oxy]pentanedioic acid;

2-[[(tetrahydrofuranyl)hydroxyphosphinyl]oxy]pentanedioic acid;

2-[[(2 -indolyl)hydroxyphosphinyl]oxy]pentanedioic acid ;

- [ [(3-indolyl)hydroxyphosphinyl]oxy]pentanedioic acid;

2-[[(4-indolyl)hydroxyphosphinyl]oxy]pentanedioic acid;

2-[[(2-thienyl)hydroxyphosphinyl]oxy]pentanedioic acid ;

2-[[(3-thienyl)hydroxyphosphinyl]oxy]pentanedioic acid;

2-[[(4-thienyl)hydroxyphosphinyl)oxy]pentanedioic acid;

2-[[(2-pyridyl)hydroxyphosphinyl]oxy]-2-phenylethanoic acid;

2-[[(3-pyridyl)hydroxyphosphinyl]oxy]-2-phenylethanoic acid;

-[[(4-pyridyl)hydroxyphosphinyl]oxy]-2-phenylethanoic acid;

2-[[tetrahydrofuranyl)hydroxyphosphinyl]oxy]-2phenylethanoic acid;

2-[[(2-indolyl)hydroxyphosphinyl]oxy]- 2-phenylethanoic acid;

2-[[(3-indolyl)hydroxyphosphinyl]oxy]-2-phenylethanoic acid;

2-[[(4-indolyl)hydroxyphosphinyl]oxy] -2-phenylethanoic acid;

2-[[(2-thienyl)hydroxyphosphinyl]oxy]-2-phenylethanoic acid;

2-[[(3-thienyl)hydroxyphosphinyl]oxy]-2-phenylethanoic acid;

2-[[(4-thienyl)hydroxyphosphinyl]oxy]-2-phenylethanoic acid;

2-[[benzylhydroxyphosphinyl]oxy]-2-(2-pyridyl)ethanoic acid;

2-[[benzylhydroxyphosphinyl]oxy]-2-(3-pyridyl)ethanoic acid;

2-[[benzylhydroxyphosphinyl]oxy]-2-(4-pyridyl)ethanoic acid;

2-[[benzylhydroxyphosphinyl]oxy]-2-(tetrahydrofuranyl) ethanoic acid;

2-[[benzylhydroxyphosphinyl]oxy]-2-(2-indolyl)ethanoic acid;

2-[[benzylhydroxyphosphinyl]oxy]-2-(3-indolyl)ethanoic acid;

2-[[benzylhydroxyphosphinyl]oxy]-2-(4-indolyl) ethanoic acid;

2-[[benzylhydroxyphosphinyl]oxy]-2-(2-thienyl)ethanoic acid;

2-[[benzylhydroxyphosphinyl]oxy]-2-(3 -thienyl)ethanoic acid;

2-[[benzylhydroxyphosphinyl]oxy]-2-(4-thienyl)ethanoic acid; and a pharmaceutically acceptable salt, hydrate, or a mixture thereof.

22. The use of claim 8, wherein R_x or R₂ is heterocyclic and X is NR_X.

23. The use of claim 22, wherein the NAALADase inhibitor is a compound selected from the group consisting of:

2-[[(2-pyridyl)hydroxyphosphinyl]amino]pentanedioic acid;

2-[[(3-pyridyl)hydroxyphosphinyl]amino]pentanedioic acid;

2-[[(4-pyridyl)hydroxyphosphinyl]amino]pentanedioic acid ; 2-[[(tetrahydrofuranyl)hydroxyphosphinyl]amino] pentanedioic acid;

-[[(2 -indolyl)hydroxyphosphinyl]amino]pentanedioic acid;

2-[[(3-indolyl)hydroxyphosphinyl]amino]pentanedioic acid;

2-[[(4-indolyl)hydroxyphosphinyl]amino]pentanedioic acid;

2-[[(2-thienyl)hydroxyphosphinyl]amino]pentaneiioic acid;

2-[[(3-thienyl)hydroxyphosphinyl]amino]pentanedioic acid;

- [ [(4-thienyl)hydroxyphosphinyl]amino]pentanedioic acid;

2-[[(2-pyridyl)hydroxyphosphinyl]amino]-2-phenylethanoic acid;

-[[(3-pyridyl)hydroxyphosphinyl]amino]-2-phenylethanoic acid;

2-[[(4-pyridyl)hydroxyphosphinyl]amino]-2-phenylethanoic acid;

2-[[(tetrahydrofuranyl)hydroxyphosphinyl]amino]-2-phenyl ethanoic acid;

2-[[(2-indolyl)hydroxyphosphinyl]amino]-2-phenylethanoic acid;

2-[[(3-indolyl)hydroxyphosphinyl]amino]- 2-phenylethanoic acid;

2-[[(4-indolyl)hydroxyphosphinyl]amino]-2-phenylethanoic acid;

2-[[(2-thienyl)hydroxyphosphinyl]amino]-2-phenylethanoic acid;

2-[[(3-thienyl)hydroxyphosphinyl]amino]-2-phenylethanoic acid;

2-[[(4-thienyl)hydroxyphosphinyl]amino]-2-phenylethanoic acid;

2-[[benzylhydroxyphosphinyl] amino]-2-(2-pyridyl)ethanoic acid;

2-[[benzylhydroxyphosphinyl]amino]-2-(3-pyridyl)ethanoic acid;

2-[[benzylhydroxyphosphinyl]amino]-2-(4-pyridyl)ethanoic acid;

2-[[benzylhydroxyphosphinyl]amino]-2-(tetrahydrofuranyl) ethanoic acid;

2-[[benzylhydroxyphosphinyl]amino]-2-(2 -indolyl)ethanoic acid;

2-[[benzylhydroxyphosphinyl]amino]-2-(3-indolyl)ethanoic acid;

2-[[benzylhydroxyphosphinyl]amino]-2-(4-indolyl)ethanoic acid;

2-[[benzylhydroxyphosphinyl]amino]-2-(2 -thienyl)ethanoic acid;

2-[[benzylhydroxyphosphinyl]amino]-2-(3-thienyl)ethanoic acid;

2-[[benzylhydroxyphosphinyl]amino]-2-(4-thienyl)ethanoic acid; and a pharmaceutically acceptable salt, hydrate, or a mixture thereof.

24. Use of a NAALADase inhibitor for inhibiting tumor celi growth in an animai suffering from a tumor celi growth.

25. The use of claim 24, wherein the tumor is prostate adenocarcinoma.

26. The use of claim 24, wherein the NAALADase inhibitor is selected from the group consisting of: a glutamate-derived hydroxyphosphinyl derivative compound; an acidic peptide analog; a conformationally restricted glutamate mimic; and mixtures thereof.

27. The use of claim 26, wherein the NAALADase inhibitor is a glutamate-derived hydroxyphosphinyl derivative compound.

28. The use of claim 24, wherein the NAALADase inhibitor is used in combination with an additional therapeutic aģent selected from the group consisting of: therapeutic hormones, chemotherapeutic hormones, antiangiogenesis aģents, radiolabelled compounds, and mixtures thereof.

29. The use of claim 24 wherein the tumor is selected from the group consisting of: ACTH-producing tumor, acute lymphocytic leukemia, acute nonlymphocytic leukemia, cancer of the adrenal cortex, bladder cancer, brain cancer, breast cancer, cervical cancer, chronic lymphocytic leukemia, chronic myelocytic leukemia, colorectal cancer, cutaneous T-cell lymphoma, endometrial cancer, esophageal cancer, Ewing's sarcoma, gallbladder cancer, hairy celi leukemia, head & neck cancer, Hodgkin's lymphoma, Kaposi’s sarcoma, kidney cancer, liver cancer, lung cancer, lung cancer (small . and/or non-small celi), malignant peritoneal effusion, malignant pleural effusion, melanoma, mesotheiioma, multiple myeloma, neuroblastoma, non-Hodgkin's lymphoma, osteosarcoma, ovary cancer, ovary (germ celi) cancer, pancreatic cancer, penis cancer, prostate adenocarcinoma, retinoblastoma, skin cancer, soft tissue sarcoma, squaraous celi carcinomas, stomach cancer, testicular cancer, thyroid cancer, trophoblastic neoplasms, cancer of the uterus, vaginai cancer, cancer of the vulva, and Wilm's tumor.

30. The use of claim 24, vvherein the tumor is prostatic adenocarcinoma.

31. The use of claim 24, vvherein the tumor is selected from the group consisting of: brain cancer, cancer of the adrenal cortex, kidney cancer, and testicular cancer.

32. The use of claim 24, vvherein the NAALADase inhibitor comprises a compound having the follovving formula:

Ri

O “P'

OH 'X

R2

COOH

Formula I, vvherein

R is hydrogen, C^-Cg straight or branched chain alkyl, C₂-C₉ straight or branched chain alkenyl group, C₃-C_a cycloalkyl, C₅-C_? cycloalkenyl, or Ar^·

X is CH₂, O, or NR_lZ vvhere R^. is defined above; and R₂ is straight or branched chain alkyl, C₂-C₉ straight or branched chain alkenyl group, C₃-C₃. cycloalkyl, C₅-C₇ cycloalkenyl, or Ar_x, vvherein said alkyl, alkenyl, cycloalkyl, cycloalkenyl or aryl group may be optionally substituted vvith carboxylic acid, vvherein said alkyl, alkenyl, cycloalkyl, cycloalkenyl or aryl groups may be optionally substituted vvith C₃-C₈cycloalkyl, C₃ or C₅ cycloalkyl, C₅-C₇ cycloalkenyl, C₃-C alkyl, ^c1^_c4 alkenyl, halo, hydroxy, carboxy, nitro, trifluoromethyl, C₁-C₆ straight or branched chain alkyl or alkenyl, C₃-C₄ alkoxy, Ο₃-Ο₄ alkenyloxy, phenoxy, benzyloxy, amino, or Ar_x, and vvhere Ar_x is selected from the group consisting of l-naphthyl, 2-naphthyl, 2-indolyl, 3-indolyl, 4-indolyl, 2-furyl, 3-furyl, tetrahydrofuranyl, 2-thienyl, 3-thienyl, 4-thienyl, 2-, 3-, or 4-pyridyl, or phenyl, having one to five substituents vvhich are independently selected from the group consisting of hydrogen, halo, hydroxy, carboxy, nitro, trifluoromethyl, C₁-C_s straight or branched alkyl or alkenyl, C₁-C₄ alkoxy or C₃-C₄ alkenyloxy, phenoxy, benzyloxy, and amino; or pharmaceutically acceptable salts, hydrates, or mixtures thereof.

33. The use of claim 32, vvherein R and R₂ are straight or branched aliphatic groups or carbocyclic groups and X is ch₂.

34. The use of claim 33, vvherein the NAALADase inhibitor is selected from the group consisting of:

2-[[methylhydroxyphosphinyl]methyl]pentanedioic acid;

2-[[ethylhydroxyphosphinyl]methyl)pentanedioic acid;

2-[[propylhydroxyphosphinyl]methyl]pentanedioic acid;

2-[[butylhydroxyphosphinyl]methyl]pentanedioic acid;

-[[cyclohexylhydroxyphosphinyl]methyl] pentanedioic acid; 2-[[(cyclohexyl)methylhydroxyphosphinyl]methyl] pentanedioic acid;

2-[[phenylhydroxyphosphinyl]methyl]pentanedioic acid;

2- [ [benzylhydroxyphosphinyl]methyl]pentanedioic acid;

2-[[phenylethylhydroxyphosphinyl]methyl]pentanedioic acid; 2-[[phenylpropylhydroxyphosphinyl]methyl]pentanedioic acid; 2-[[phenylbutylhydroxyphosphinyl]methyl]pentanedioic acid;

— [ [(4-methylbenzyl)hydroxyphosphinyl]methyl]pentanedioic acid;

2-[[(4-fluorobenzyl)hydroxyphosphinyl]methyl]pentanedioic acid ;

2-[[(2-fluorobenzyl)hydroxyphosphinyl]methyl]pentanedioic acid;

- [ [(pentafluorobenzyl)hydroxyphosphinyl]methyl] pentanedioic acid;

2-[[(methoxybenzyl)hydroxyphosphinyl]methyl]pentanedioic acid;

2-[[(2,3,4-trimethoxyphenyl)hydroxyphosphinyl]methyl] pentanedioic acid;

2-[[(l-naphthyl)hydroxyphosphinyl]methyl]pentanedioic acid; 2-[[(2-naphthyl)hydroxyphosphinyl]methyl]pentanedioic acid; 2-[[(l-naphthyl)methylhydroxyphosphinyl]methyl] pentanedioic acid;

2-[[(2-naphthyl)methylhydroxyphosphinyl]methyl] pentanedioic acid;

2-[[(l-naphthyl)ethylhydroxyphosphinyl]methyl]pentanedioic acid;

- [ [ (2-naphthyl)ethylhydroxyphosphinyl]methyl]pentanedioic acid;

2-[[(l-naphthyl)propylhydroxyphosphinyl]methyl] pentanedioic acid;

- [ [(2-naphthyl)propylhydroxyphosphinyl]methyl] pentanedioic acid;

-[[(l-naphthyl)butylhydroxyphosphinyl]methyl]pentanedioic acid;

2-[[(2-naphthyl)butylhydroxyphosphinyl]methyl]pentanedioic acid;

- [ [ (phenylprop-2-enyl)hydroxyphosphinyl]methyl] pentanedioic acid;

2-[[(2 -fluorobenzyl)hydroxyphosphinyl]methyl]pentanedioic acid;

2- [ [(4-fluorophenyl)hydroxyphosphinyl]methyl]pentanedioic acid;

-[[((hydroxy)phenylmethyl)hydroxyphosphinyl]methyl] pentanedioic acid;

- [ [(3-methylbenzyl)hydroxyphosphinyl]methyl]pentanedioic acid;

2- (phosphonomethyl)pentanedioic acid;

- [ [ (3 - trif lu.oromethylbenzyl) hydroxyphosphinyl] methyl] pentanedioic acid;

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-phenylpropanoic acid; 3- (phenylbu.tylhydroxyphosphinyl) -2-phenylpropanoic acid;

3- ( (2,3,4-trimethoxyphenyl)-3-hydroxyphosphinyl)-2phenylpropanoic acid;

3-((l-ņaphthyl)hydroxyphosphinyl)-2-phenylpropanoic acid; 3-((2-naphthyl)hydroxyphosphinyl)-2-phenylpropanoic acid; 3-((l-naphthyl)methylhydroxyphosphinyl)-2-phenyl propanoic acid;

3-((2-naphthyl)methylhydroxyphosphinyl)-2-phenyl propanoic acid;

3-((l-naphthyl)ethylhydroxyphosphinyl)-2-phenylpropanoic acid;

3-((2-naphthyl)ethylhydroxyphosphinyl)-2-phenylpropanoic acid;

3-((l-naphthyl)propylhydroxyphosphinyl)-2-phenylpropanoic acid;

3-((2-naphthyl)propylhydroxyphosphinyl)-2-phenylpropanoic acid;

3-((1-naphthyl)butylhydroxyphosphinyl)-2-phenylpropanoic acid;

3-((2-naphthyl)butylhydroxyphosphinyl)-2-phenylpropanoic acid;

3-(phenylprop-2-enylhydroxyphosphinyl)-2-phenylpropanoic acid;

2-[(benzylhydroxyphosphinyl)methyl] pentanedioic acid;

-[(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]octanedioic acid;

2-[(methylhydroxyphosphinyl)methyl]nonanedioic acid;

2-[(benzylhydroxyphosphinyl)methyl]nonanedioic acid;

2-[(methylhydroxyphosphinyl)methyl]decanedioic acid;

2- [(benzylhydroxyphosphinyl)methyl]decanedioic acid;

3- (benzylhydroxyphosphinyl)-2-methylpropanoic acid;

3-(benzylhydroxyphosphinyl)-2-ethylpropanoic acid;

3-(benzylhydroxyphosphinyl)-2-propylpropanoic acid;

3-(benzylhydroxyphosphinyl)-2-butylpropanoic acid;

3-(benzylhydroxyphosphinyl)-2-cyclohexylpropanoic acid;

3-(benzylhydroxyphosphinyl)-2-(cyclohexyl)methylpropanoic acid;

3-(benzylhydroxyphosphinyl)-2-phenylpropanoic acid;

3-(benzylhydroxyphosphinyl)-2-benzylpropanoic acid;

3-(benzylhydroxyphosphinyl)-2-phenylethylpropanoic acid;

3-(benzylhydroxyphosphinyl)-2-(2,3,4-trimethoxyphenyl) propanoic acid;

3-(benzylhydroxyphosphinyl)-2-(l-naphthyl)propanoic acid; 3-(benzylhydroxyphosphinyl)-2-(2-naphthyl)propanoic acid; 3-(benzylhydroxyphosphinyl)-2-(l-naphthyl)methylpropanoic acid;

3-(benzylhydroxyphosphinyl)-2-(2-naphthyl)methylpropanoic acid;

3-(benzylhydroxyphosphinyl)-2-(l-naphthyl)ethylpropanoic acid;

3-(benzylhydroxyphosphinyl)-2-(2-naphthyl)ethylpropanoic acid;

3-(benzylhydroxyphosphinyl)-2-(1-naphthyl)propyl propanoic acid;

3-(benzylhydroxyphosphinyl)-2-(2-naphthyl)propyl propanoic acid;

3-(benzylhydroxyphosphinyl)-2-(l-naphthyl)butylpropanoic acid;

3-(benzylhydroxyphosphinyl)-2-(2-naphthyl)butylpropanoic acid;

3-(benzylhydroxyphosphinyl)-2-phenylprop-2-enylpropanoic acid;

2-[[(2-pyridyl)methylhydroxyphosphinyl]methyl]pentanedioic acid;

2-[[(3-pyridylmethylhydroxyphosphinyl]methyl]pentanedioic acid;

2-[[(4-pyridyl)methylhydroxyphosphinyl]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)ethyihydroxyphosphinyl]methyl] pentanedioic acid;

2-[[(tetrahydrofuranyl)propylhydroxyphosphinyl]methyl] pentanedioic acid;

-[[(2 -indolyl)methylhydroxyphosphinyl]methyl]pentanedioic acid;

-[[(3 -indolyl)methylhydroxyphosphinyl]methyl] pentanedioic acid;

2-[[(4-indolyl)methylhydroxyphosphinyl]methyl]pentanedioic acid;

2-[[(3-indolyl)ethylhydroxyphosphinyl]methyl]pentanedioic acid;

2-[[(3-indolyl)propylhydroxyphosphinyl]methyl]pentanedioic acid;

- [ [(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-pyridyl)methylhydroxyphosphinyl]-2-phenylpropanoic acid;

3-[[(3-pyridyl)methylhydroxyphosphinyl]-2-phenylpropanoic acid;

-[[(4-pyridyl)methylhydroxyphosphinyl]-2-phenylpropanoic acid;

3-[[(3-pyridyl)ethylhydroxyphosphinyl]-2-phenylpropanoic acid;

3-[[(3-pyridyl)propylhydroxyphosphinyl]-2-phenylpropanoic acid;

3-[[(tetrahydrofuranyl)methylhydroxyphosphinyl]-2-phenyl propanoic acid;

3-[[(tetrahydrofuranyl)ethylhydroxyphosphinyl]-2-phenyl propanoic acid;

3-[[(tetrahydrofuranyl)propylhydroxyphosphinyl]-2-phenyl propanoic 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-phenylpropanoic acid;

3-(benzylhydroxyphosphinyl)-2-(2-pyridyl)methylpropanoic acid;

3-(benzylhydroxyphosphinyl)-2-(3-pyridyl)methylpropanoic acid;

3- (benzylhydroxyph.osph.inyl) -2- (4-pyridyl) methylpropanoic acid;

3-(benzylhydroxyphosphinyl)-2-(3-pyridyl)ethylpropanoic acid;

3-(benzylhydroxyphosphinyl)-2-(3-pyridyl)propylpropanoic acid;

3-(benzylhydroxyphosphinyl)-2-(tetrahydrofuranyl)methyl propanoic acid;

3-(benzylhydroxyphosphinyl)-2-(tetrahydrofuranyl)ethyl propanoic acid;

3-(benzylhydroxyphosphinyl)-2-(tetrahydrofuranyl)propyl propanoic 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)ethylpropanoic 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; and a pharmaceutically acceptable salt, hydrate, or a mixture thereof.

35. The use of claim 33, vvherein the NAALADase inhibitor is selected from the group consisting of:

2-[(benzylhydroxyphosphinyl)methyl]pentanedioic 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)hydroxyphosphinyl]methyl]pentanedioic acid;

2-[(methylhydroxyphosphinyl)methyl]pentanedioic acid;

2-[(phenylethylhydroxyphosphinyl)methyl]pentanedioic acid; 2-[[(4-methylbenzyl;hydroxyphosphinyl]methyl]pentanedioic acid;

2-[[(4-fluorobenzyl)hydroxyphosphinyl]methylipentanedioic acid;

2-[[(4-methoxybenzyl)hydroxyphosphinyl]methyl]pentanedioic acid;

2-(phosphonomethyl)pentanedioic acid;

2-[[(3-trifluoromethylbenzyl)hydroxyphosphinyl]methyl] pentanedioic acid;

2-[[(2-fluorobenzyl)hydroxyphosphinyl]methyl]pentanedioic acid;

2-[[(pentafluorobenzyl)hydroxyphosphinyl]methyl] pentanedioic acid; and a pharmaceutically acceptable salt, hydrate, or a mixture thereof.

36. The use of claim 32, vvherein R_x and R₂ are straight or branched or carbocyclic groups and X is oxygen.

37. The use of claim 36, vvherein che NAALADase inhibitor is selected from the group consisting of:.

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 ;

-[[phenylbutylhydroxyphosphinyl]oxy]pentanedioic acid;

2-[[(4-methylbenzyl)hydroxyphosphinyl]oxy]pentanedioic acid;

- [ [ (4-fluorobenzyl)hydroxyphosphinyl]oxy]pentanedioic acid;

2-[[(2-fluorobenzyl)hydroxyphosphinyl]oxy)pentanedioic acid;

2-[ [ (pentafluorobenzyl)hydroxyphosphinyl]oxy]pentanedioic acid;

- [ [(methoxybenzyl)hydroxyphosphinyl]oxy]pentanedioic acid;

-[[(2,3,4 -trimethoxyphenyl)hydroxyphosphinyl]oxy] pentanedioic acid;

2-[[(l-naphthyl)hydroxyphosphinyl]oxy]pentanedioic acid; 2-[[(2-naphthyl)hydroxyphosphinyl]oxy]pentanedioic acid; 2-[[(l-naphthyl)methylhydroxyphosphinyl]oxy]pentanedioic acid;

2-[((2-naphthyl)methylhydroxyphosphinyl]oxy]pentanedioic acid;

2-[[(l-naphthyl)ethylhydroxyphosphinyl]oxy]pentanedioic acid;

2-[[(2-naphthyl)ethylhydroxyphosphinyl]oxy]pentanedioic acid;

— [ [(l-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-[[(2-fluorobenzyl)hydroxyphosphinyl]oxy]pentanedioic acid;

2-[[(4-fluorophenyl)hydroxyphosphinyl]oxy]pentanedioic acid;

2-[[((hydroxy)phenylmethyl)hydroxyphosphinyl]methyl] pentanedioic acid;

2-[[(3-methylbenzyl)hydroxyphosphinyl]methyl]pentanedioic acid;

2-[(phosphono)oxy]pentanedioic acid;

2-[[(3-trifluoromethylbenzyl)hydroxyphosphinyl]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-phenylethanoic acid;

2-[[phenylhydroxyphosphinyl]oxy]-2-phenylethanoic acid;

2-[[benzylhydroxyphosphinyl]oxy]-2-phenylethanoic acid;

2-[[phenylethylhydroxyphosphinyl]oxy]-2-phenylethanoic acid;

2-[[phenylpropylhydroxyphosphinyl]oxy]-2-phenylethanoic acid;

2-[[phenylbutylhydroxyphosphinyl]oxy]-2-phenylethanoic acid ;

- [ [ (2,3,4-trimethoxyphenyl)-3-hydroxyphosphinyl]oxy]-2phenylethanoic acid;

2-[[(l-naphthyl)hydroxyphosphinyl]oxy]-2-phenylethanoic acid;

2- [ [(2-naphthyl)hydroxyphosphinyl]oxy]-2-phenylethanoic acid;

-[[(l-naphthyl)methylhydroxyphosphinyl)]oxy]-2phenylethanoic acid;

2-[[(2-naphthyl)methylhydroxyphosphinyl]oxy]-2phenylethanoic acid;

2-[[(l-naphthyl)ethylhydroxyphosphinyl]oxy]-2phenylethanoic acid;

2-[[(2-naphthyl)ethylhydroxyphosphinyl]oxy]-2phenylethanoic acid;

2-[[(l-naphthyl)propylhydroxyphosphinyl]oxy]-2LV 12253 phenylethanoic acid;

2-[[(2-naphthyl)propylhydroxyphosphinyl]oxy]-2phenylethanoic acid;

2-[[(l-naphthyDbutylhydroxyphosphinyl]oxy]-2-phenyl ethanoic acid;

2-[[(2-naphthyl)butylhydroxyphosphinyl]oxy]-2-phenyl ethanoic acid;

2-[[phenylprop-2-enylhydroxyphosphinyl]oxy]-2-phenyl ethanoic acid;

2-[(methylhydroxyphosphinyl)oxy]hexanedioic acid;

2-[(benzylhydroxyphosphinyl)oxy] hexanedioic acid;

2-[(methylhydroxyphosphinyl)oxy]heptanedioic acid;

2- [ (benzylhydroxyphosphinyl)oxy]heptanedioic acid;

2-((methylhydroxyphosphinyl)oxy]octanedioic acid;

2-[(benzylhydroxyphosphinyl)oxy]octanedioic acid;

2-[(methylhydroxyphosphinyl)oxy]nonanedioic acid;

2-[(benzylhydroxyphosphinyl)oxy]nonanedioic acid;

2-[(methylhydroxyphosphinyl)oxy]decanedioic acid;

2-[(benzylhydroxyphosphinyl)oxy]decanedioic acid;

2-[[benzylhydroxyphosphinyl]oxy]-2-methylethanoic acid;

2-[[benzylhydroxyphosphinyl]oxy]-2-ethylethanoic acid;

2-[[benzylhydroxyphosphinyl]oxy]-2-propylethanoic acid;

2-[[benzylhydroxyphosphinyl]oxy]-2-butylethanoic acid;

2-[[benzylhydroxyphosphinyl]oxy]-2-cyclohexylethanoic acid; 2-[[benzylhydroxyphosphinyl]oxy]-2-cyclohexyl)methyl ethanoic acid;

2-[[benzylhydroxyphosphinyl]oxy]-2-phenylethanoic acid;

2-[[benzylhydroxyphosphinyl]oxy]-2-benzylethanoic acid;

2-[[benzylhydroxyphosphinyl]oxy]-2-phenylethylethanoic acid;

2-[[benzylhydroxyphosphinyl]oxy]-2-phenylpropylethanoic acid;

2-[[benzylhydroxyphosphinyl]oxy]-2-phenylbutylethanoic acid;

-[[benzylhydroxyphosphinyl]oxy]-2 -(2,3,4trimethoxyphenyl)ethanoic acid;

2-[[benzylhydroxyphosphinyl]oxy]-2-(l-naphthyl)ethanoic acid;

2-[[benzylhydroxyphosphinyl]oxy]-2-(2-naphthyl)ethanoic acid;

2-[[benzylhydroxyphosphinyl]oxy]-2-(1-naphthyl)methyl ethanoic acid;

2-[[benzylhydroxyphosphinyl]oxy]-2-(2-naphthyl)methyl ethanoic acid;

2-[[benzylhydroxyphosphinyl]oxy]-2-(l-naphthyl)ethyl ethanoic acid;

2-[[benzylhydroxyphosphinyl]oxy]-2-(2-naphthyl)ethyl ethanoic acid;

2-[[benzylhydroxyphosphinyl]oxy]-2-(l-naphthyl)propyl ethanoic acid;

2-[[benzylhydroxyphosphinyl]oxy]-2-(2-naphthyl)propyl ethanoic acid;

2-[[benzylhydroxyphosphinyl]oxy]-2-(l-naphthyl)butyl ethanoic acid;

2-[[benzylhydroxyphosphinyl]oxy]-2-(2-naphthyl)butyl ethanoic acid;

2-[[benzylhydroxyphosphinyl]oxy]-2-phenylprop-2enylethanoic acid;

2-[[(2-pyridyl)methylhydroxyphosphinyl]oxy]pentanedioic acid;

2-[[(3-pyridyl)methylhydroxyphosphinyl]oxy]pentanedioic acid;

2-[[(4-pyridyl)methylhydroxyphosphinyl]oxy]pentanedioic acid;

- [ [ (3-pyridyl)ethylhydroxyphosphinyl]oxy]pentanedioic acid;

2-[[(3-pyridyl)propylhydroxyphosphinyl]oxy]pentanedioic acid;

2-[[(tetrahydrofuranyl)methylhydroxyphosphinyl]oxy] pentanedioic acid;

- [ [ (tetrahydrofuranyl)ethylhydroxyphosphinyl]oxy] pentanedioic acid;

2-[[(tetrahydrofuranyl)propylhydroxyphosphinyl]oxy] pentanedioic acid;

2-[[(2-indolyl)methylhydroxyphosphinyl]oxy]pentanedioic acid;

- [ [ (3 -indolyl)methylhydroxyphosphinyl]oxy]pentanedioic acid;

2- [ [ (4-indolyl)methylhydroxyphosphinyl]oxy]pentanedioic acid;

- [ [(3-indolyl)ethylhydroxyphosphinyl]oxy]pentanedioic acid;

2-[[(3-indolyl)propylhydroxyphosphinyl]oxy]pentanedioic acid;

2-[[(2-thienyl)methylhydroxyphosphinyl]oxy]pentanedioic acid;

2-[[(3-thienyl)methylhydroxyphosphinyl]oxy]pentanedioic acid;

2-[[(4-thienyl)methylhydroxyphosphinyl]oxy]pentanedioic acid;

-[[(3-thienyl)ethylhydroxyphosphinyl]oxy]pentanedioic acid;

- [ [ (3-thienyl)propylhydroxyphosphinyl]oxy]pentanedioic acid;

2-[[(2-pyridyl)methylhydroxyphosphinyl]oxy]-2-phenyl ethanoic acid;

-[[(3-pyridyl)methylhydroxyphosphinyl]oxy]-2-phenyl ethanoic acid;

- [ [(4-pyridyl)methylhydroxyphosphinyl]oxy]-2-phenyl ethanoic acid;

2-[[(3-pyridyl)ethylhydroxyphosphinyl]oxy]-2-phenyl ethanoic acid;

2-[[(3-pyridyl)propylhydroxyphosphinyl]oxy]-2-phenyl ethanoic acid;

2-[[(tetrahydrofuranyl)methylhydroxyphosphinyl]oxy]-2phenyl ethanoic acid;

2-[[(tetrahydrofuranyl)ethylhydroxyphosphinyl]oxy]-2phenylethanoic acid;

2-[[(tetrahydrofuranyl)propylhydroxyphosphinyl]oxy]-2phenylethanoic acid;

- [ [(2-indolyl)methylhydroxyphosphinyl]oxy]-2-phenyl ethanoic acid;

- [ [(3-indolyl)methylhydroxyphosphinyl]oxy]-2-phenyl ethanoic acid;

-[[(4-indolyl)methylhydroxyphosphinyl]oxy]-2-phenyl ethanoic acid;

-[[(3-indolyl)ethylhydroxyphosphinyl]oxy]-2-phenyl ethanoic acid;

2-[[(3-indolyl)propylhydroxyphosphinyl]oxy]-2-phenyl ethanoic acid;

2-[[(2-thienyl)methylhydroxyphosphinyl]oxy]-2-phenyl ethanoic acid;

2-[[(3 -thienyl)methylhydroxyphosphinyljoxy]-2-phenyl ethanoic acid;

2-[E(4-thienyl)methylhydroxyphosphinyl]oxy]-2-phenyl ethanoic acid;

-[[(3-thienyl)ethylhydroxyphosphinyl]oxy]-2-phenyl ethanoic acid;

2-[[(3 -thienyl)propylhydroxyphosphinyl]oxy]-2-phenyl ethanoic acid;

2-[[benzylhydroxyphosphinyl]oxy]-2-(2-pyridyl)methyl ethanoic acid;

2-[[benzylhydroxyphosphinyl]oxy]-2-(3-pyridyl)methyl ethanoic acid;

2-[[benzylhydroxyphosphinyl]oxy]-2-(4-pyridyl)methyl ethanoic acid;

2-[[benzylhydroxyphosphinyl]oxy]-2-(3-pyridyl)ethyl ethanoic acid;

2-[[benzylhydroxyphosphinyl]oxy]-2-(3-pyridyl)propyl ethanoic acid;

2-[[benzylhydroxyphosphinyl]oxy]-2-(tetrahydrafuranyl) methylethanoic acid;

2-[[benzylhydroxyphosphinyl]oxy]-2-(tetrahydrafuranyl) ethylethanoic acid;

2-[[benzylhydroxyphosphinyl]oxy]-2-(tetrahydrafnranyl) propylethanoic acid;

2-[[benzylhydroxyphosphinyl]oxy]-2-(2-indolyl)methyl ethanoic acid;

2-[[benzylhydroxyphosphinyl]oxy]-2-(3-indolyl)methyl ethanoic acid;

2-[[benzylhydroxyphosphinyl]oxy]-2-(4 -indolyl)methyl ethanoic acid;

2-[[benzylhydroxyphosphinyl]oxy]-2-(3 -indolyl)ethyl ethanoic acid;

2-[[benzylhydroxyphosphinyl]oxy]-2-(3-indolyl)propyl ethanoic acid;

2-[[benzylhydroxyphosphinyl]oxy]-2-(2 -thienyl)methyl ethanoic acid;

2-[[benzylhydroxyphosphinyl]oxy]-2-(3-thienyl)methyl ethanoic acid;

2-[[benzylhydroxyphosphinyl]oxy]-2-(4 -thienyl)methyl ethanoic acid;

2-[[benzylhydroxyphosphinyl]oxy]-2-(3-thienyl)ethyl ethanoic acid;

2-[[benzylhydroxyphosphinyl]oxy]-2-(3-thienyl)propyl ethanoic acid; and a pharmaceutically acceptable salt, hydrate, or a mixture thereof.

38. The use of claim 36, wherein the NAALADase inhibitor is selected from the group consisting of:

2-[(benzylhydroxyphosphinyl)oxy]pentanedioic acid;

2-[(phenylhydroxyphosphinyl)oxy]pentanedioic acid;

-[[((hydroxy)phenylmethyl)hydroxyphosphinyl]oxy] pentanedioic acid;

2-[(butylhydroxyphosphinyl)oxy]pentanedioic acid;

2-[[(3-methylbenzyl)hydroxyphosphinyl]oxy]pentanedioic acid;

2-[(methylhydroxyphosphinyl)oxy]pentanedioic acid;

2-[(phenylethylhydroxyphosphinyl)oxy]pentanedioic acid;

-[[(4-methylbenzyl)hydroxyphosphinyl]oxy]pentanedioic acid;

2-[[(4 -fluorobenzyl)hydroxyphosphinyl]oxy]pentanedioic acid;

2-[[(4-methoxybenzyl)hydroxyphosphinyl]oxy]pentanedioic acid;

2- [ (phosphono)oxy]pentanedioic acid;

2-[[(3-trifluoromethylbenzyl)hydroxyphosphinyl]oxy] pentanedioic acid;

2-[[(2-fluorobenzyl)hydroxyphosphinyl]oxy]pentanedioic acid;

2-[[(pentafluorobenzyl)hydroxyphosphinyl]oxy]pentanedioic acid; and a pharmaceutically acceptable salt, hydrate, or a mixture thereof.

39. The use of claim 32, vvherein and R₂ are straight or branched or carbocyclic and X is NR_X.

40. The use of claim 39, vvherein the NAALADase inhibitor is selected from the group consisting of:

2-[[methylhydroxyphosphinyl]amino]pentanedioic acid;

2-[[ethylhydroxyphosphinyl]amino]pentanedioic acid;

2-[[propylhydroxyphosphinyl]amino]pentanedioic acid;

2-[[butylhydroxyphosphinyl]amino]pentanedioic acid;

2-[[cyclohexylhydroxyphosphinyl]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;

-[[phenylbutylhydroxyphosphinyl]amino]pentanedioic acid;

2-[[(4-methylbenzyl)hydroxyphosphinyl]amino]pentanedioic acid;

2-[[(4 -fluorobenzyl)hydroxyphosphinyl]amino]pentanedioic acid;

-[[(2-fluorobenzyl)hydroxyphosphinyl]amino]pentanedioic acid;

2-[[(pentafluorobenzyl)hydroxyphosphinyl]amino] pentanedioic acid;

2-[[(methoxybenzyl)hydroxyphosphinyl]amino]pentanedioic acid;

2-[[(2,3,4-trimethoxyphenyl)hydroxyphosphinyl]amino] pentanedioic acid;

2-[[(l-naphthyl)hydroxyphosphinyl]amino]pentanedioic acid;

2-[[(2-naphthyl)hydroxyphosphinyl]amino]pentanedioic acid; 2 - [ [ (l-naphthyl)methylhydroxyphosphinyl]amino] pentanedioic acid;

2-[[(2-naphthyl)methylhydroxyphosphinyl]amino]pentanedioic acid;

2-[[(l-naphthyl)ethylhydroxyphosphinyl]amino]pentanedioic acid;

2- [ [(2-naphthyl)ethylhydroxyphosphinyl]amino]pentanedioic acid;

2- [ [(l-naphthyl)propylhydroxyphosphinyl]amino]pentanedioic acid;

2-[ [ (2-naphthyl)propylhydroxyphosphinyl]amino]pentanedioic acid;

2-[[(l-naphthyl)butylhydroxyphosphinyl]amino]pentanedioic acid;

2-[[(2-naphthyl)butylhydroxyphosphinyl]amino]pentanedioic acid;

- [ [(phenylprop-2-enyl)hydroxyphosphinyl]amino] pentanedioic acid;

2-[[benzylhydroxyphosphinyl]amino]pentanedioic acid;

2-[[(2-fluorobenzyl)hydroxyphosphinyl]amino]pentanedioic acid;

-[[((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]-2-phenylethanoic acid;

2-[[ethylhydroxyphosphinyl]amino]-2-phenylethanoic acid;

2-[[cyclohexylhydroxyphosphinyl]amino]-2-phenylethanoic acid;

2-[[(cyclohexyl)methylhydroxyphosphinyl]amino]-2-phenyl ethanoic acid;

2-[[phenylhydroxyphosphinyl]amino]-2-phenylethanoic acid; 2-[[benzylhydroxyphosphinyl]amino]-2-phenylethanoic acid; 2-[[phenylethylhydroxyphosphinyl]amino]-2-phenylethanoic acid;

2-[[phenylpropylhydroxyphosphinyl]amino]-2-phenylethanoic acid;

2-[[phenylbutylhydroxyphosphinyl]amino]-2-phenylethanoic acid;

-[[(2,3,4 -trimethoxyphenyl)-3-hydroxyphosphinyl]amino]-2 phenylethanoic acid;

2-[[(l-naphthyl)hydroxyphosphinyl]amino]-2-phenylethanoic acid;

- [ [(2-naphthyl)hydroxyphosphinyl]amino]-2-phenylethanoic acid;

2-[[(l-naphthyl)methylhydroxyphosphinyl)]amino]-2-phenyl ethanoic acid;

2-[[(2-naphthyl)methylhydroxyphosphinyl]amino]-2-phenyl ethanoic acid;

2-[[(l-naphthyl)ethylhydroxyphosphinyl]amino]-2-phenyl ethanoic acid;

2-[[(2-naphthyl)ethylhydroxyphosphinyl}amino]-2-phenyl ethanoic acid;

2-[[(l-naphthyl)propylhydroxyphosphinyl]amino]-2-phenyl ethanoic acid;

2-[[(2-naphthyl)propylhydroxyphosphinyl]amino]-2-phenyl ethanoic acid;

2-[[(l-naphthyl)butylhydroxyphosphinyl]amino]-2-phenyl ethanoic acid;

- [ [ (2-naphthyl)butylhydroxyphosphinyl]amino]-2-phenyl ethanoic acid;

2-[[phenylprop-2-enylhydroxyphosphinyl]amino]-2-phenyl ethanoic acid;

2-[[benzylhydroxyphosphinyl]amino]-2-methylethanoic acid; 2-[[benzylhydroxyphosphinyl]amino]-2-ethylethanoic acid; 2-[[benzylhydroxyphosphinyl]amino]-2-propylethanoic acid; 2-[[benzylhydroxyphosphinyl]amino]-2-butylethanoic acid; 2-[[benzylhydroxyphosphinyl]amino]-2-cyclohexylethanoic acid;

2-[ [benzylhydroxyphosphinyl]amino]-2-(cyclohexyl)methyl ethanoic acid;

2-[[benzylhydroxyphosphinyl]amino]-2-phenylpropylethanoic acid;

2-[[benzylhydroxyphosphinyl]amino]-2-phenylbutylethanoic acid;

-[ [benzylhydroxyphosphinyl]amino]-2 -(2,3,4trimethoxyphenyl)ethanoic acid;

2-[[benzylhydroxyphosphinyl]amino]-2-(l-naphthyl)ethanoic acid;

2-[[benzylhydroxyphosphinyl]amino]-2-(2-naphthyl)ethanoic acid;

2-[[benzylhydroxyphosphinyl]amino]-2-(l-naphthyl)methyl ethanoic acid;

2-[[benzylhydroxyphosphinyl]amino]-2-(2-naphthyl)methyl ethanoic acid;

2-[[benzylhydroxyphosphinyl]amino]-2-(l-naphthyl)ethyl ethanoic acid;

2-[[benzylhydroxyphosphinyl]amino]-2-(2-naphthyl)ethyl ethanoic acid;

2- [ [benzylhydroxyphosphinyl]amino]-2-(l-naphthyl)propyl ethanoic acid;

2-[[benzylhydroxyphosphinyl]amino]-2-(2-naphthyl)propyl ethanoic acid;

2-[[benzylhydroxyphosphinyl]amino]-2-(l-naphthyl)butyl ethanoic acid;

2-[[benzylhydroxyphosphinyl]amino]-2-(2-naphthyl)butyl ethanoic acid;

2-[[benzylhydroxyphosphinyl]amino]-2-phenolprop-2-enyl ethanoic 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]nonanedioic acid;

2- [ (benzylhydroxyphosphinyl)amino]nonanedioic acid;

2- [ (methylhydroxyphosphinyl)amino]decanedioic acid;

2-[(benzylhydroxyphosphinyl)amino]decanedioic acid;

2-[[(2-pyridyl)methylhydroxyphosphinyl]amino]pentanedioic acid;

2-[[(3-pyridyl)methylhydroxyphosphinyl]amino]pentanedioic acid;

2-[[(4-pyridyl)methylhydroxyphosphinyl]amino]pentanedioic acid;

2-[[(3-pyridyl)ethylhydroxyphosphinyl]amino]pentanedioic acid;

2-[[(3-pyridyl)propylhydroxyphosphinyl]amino]pentanedioic acid;

2-[[(tetrahydrofuranyl)methylhydroxyphosphinyl]amino] pentanedioic acid;

2-[[(tetrahydrofuranyl)ethylhydroxyphosphinyl]amino] pentanedioic acid;

2-[[(tetrahydrofuranyl)propylhydroxyphosphinyl]amino] pentanedioic acid;

2-[[(2 -indolyl)methylhydroxyphosphinyl]amino]pentanedioic acid;

2-[[(3-indolyl)methylhydroxyphosphinyl]amino]pentanedioic acid;

2-[[(4-indolyl)methylhydroxyphosphinyl]amino]pentanedioic acid;

-[[(3 -indolyl)ethylhydroxyphosphinyl]amino]pentanedioic acid;

2-[[(3-indolyl)propylhydroxyphosphinyl]amino]pentanedioic acid;

2-[[(2-thienyl)methylhydroxyphosphinyl]amino]pentanedioic acid;

2-[[(3-thienyl)methylhydroxyphosphinyl]amino]pentanedioic acid;

2-[[(4-thienyl)methylhydroxyphosphinyl]amino]pentanedioic acid;

2-[[(3-thienyl)ethylhydroxyphosphinyl]amino]pentanedioic acid;

2-[[(3-thienyl)propylhydroxyphosphinyl]amino]pentanedioic acid; .

2-[[(2-pyridyl)methylhydroxyphosphinyl]amino]-2-phenyl ethanoic acid;

2-[[(3-pyridyl)methylhydroxyphosphinyl]amino]-2-phenyl ethanoic acid;

2-[[(4-pyridyl)methylhydroxyphosphinyl]amino]-2-phenyl ethanoic acid;

2-[[(3-pyridyl)ethylhydroxyphosphinyl]amino]-2-phenyl ethanoic acid;

2-[[(3-pyridyl)propylhydroxyphosphinyl]amino]-2-phenyl ethanoic acid;

2-[[(tetrahydrofurany)methylhydroxyphosphinyl]amino]-2phenylethanoic acid;

2-[[(tetrahydrofuranyl)ethylhydroxyphosphinyl]amino]-2phenylethanoic acid;

2-[[(tetrahydrofuranyl)propylhydroxyphosphinyl]amino]-2phenylethanoic acid;

2-[[(2-indolyl)methylhydroxyphosphinyl]amino]-2-phenyl ethanoic acid;

2-[[(3-indolyl)methylhydroxyphosphinyl]amino]-2-phenyl ethanoic acid;

2-[[(4-indolyl)methylhydroxyphosphinyl]amino]-2-phenyl ethanoic acid;

-[[(3 -indolyl)ethylhydroxyphosphinyl]amino]-2-phenyl ethanoic acid;

2-[[(3-indolyl)propylhydroxyphosphinyl]amino]-2-phenyl ethanoic acid;

-[[(2-thienyl)methylhydroxyphosphinyl]amino]-2-phenyl ethanoic acid;

2-[[(3-thienyl)methylhydroxyphosphinyl]amino]-2-phenyl ethanoic acid;

2-[[(4-thienyl)methylhydroxyphosphinyl]amino]-2-phenyl ethanoic acid;

2-[[(3-thienyl)ethylhydroxyphosphinyl]amino]-2-phenyl ethanoic acid;

2-[[(3-thienyl)propylhydroxyphosphinyl]amino]-2-phenyl ethanoic acid;

2-[ [benzylhydroxyphosphinyl]amino]-2-(2-pyridyl)methyl ethanoic acid;

2- [ [benzylhydroxyphosphinyl]amino]-2-(3-pyridyl)methyl ethanoic acid;

2-[[benzylhydroxyphosphinyl]amino]-2-(4-pyridyl)methyl ethanoic acid;

2-[[benzylhydroxyphosphinyl]amino]-2-(3-pyridyl)ethyl ethanoic acid;

2-[[benzylhydroxyphosphinyl]amino]-2-(3-pyridyl)propyl ethanoic acid;

2-[[benzylhydroxyphosphinyl]amino]-2-(tetrahydrafuranyl) methylethanoic acid;

2-[[benzylhydroxyphosphinyl]amino]-2-(tetrahydrafuranyl) ethylethanoic acid;

2-[[benzylhydroxyphosphinyl]amino]-2-(tatrahydrafuranyl) propylethanoic acid;

2-[[benzylhydroxyphosphinyl]amino]-2-(2-indolyl)methyl ethanoic acid;

2-[[benzylhydroxyphosphinyl]amino]-2-(3 -indolyl)methyl ethanoic acid;

2-[[benzylhydroxyphosphinyl]amino]-2-(4 -indolyl)methyl ethanoic acid;

2-[[benzylhydroxyphosphinyl]amino]-2-(3-indolyl)ethyl ethanoic acid;

2-[[benzylhydroxyphosphinyl]amino]-2-(3 -indolyl)propyl ethanoic acid;

2-[[benzylhydroxyphosphinyl]amino]-2-(2-thienyl)methyl ethanoic acid;

2-[[benzylhydroxyphosphinyl]amino]-2-(3 -thienyl)methyl ethanoic acid;

2-[[benzylhydroxyphosphinyl]amino]-2-(4-thienyl)methyl ethanoic acid;

2-[[benzylhydroxyphosphinyl]amino]-2-(3-thienyl)ethyl ethanoic acid;

41. The use of claim 39, wherein the NAALADase inhibitor is selected from the group consisting of:

2-[(benzylhydroxyphosphinyl)amino]pentanedioic acid;

2-[(phenylhydroxyphosphinyl)amino]pentanedioic acid;

-[[((hydroxy)phenylmethyl)hydroxyphosphinyl]amino] pentanedioic acid;

2- [ (butylhydroxyphosphinyl)amino]pentanedioic acid;

2-[[(3-methylbenzyl)hydroxyphosphinyl]amino]pentanedioic acid;

2-[(3-phenylpropylhydroxyphosphinyl)amino]pentanedioic acid;

2-[[(4-fluorophenyl)hydroxyphosphinyl]amino]pentanedioic acid;

2-[(methylhydroxyphosphinyl)amino]pentanedioic acid;

-[(phenylethylhydroxyphosphinyl)amino]pentanedioic acid;

2-[[(4-methylbenzyl)hydroxyphosphinyl]amino]pentanedioic acid;

2-[[(4 -fluorobenzyl)hydroxyphosphinyl]amino]pentanedioic acid;

2-[[(4-methoxybenzyl)hydroxyphosphinyl] amino]pentanedioic acid;

2- [ (phosphono)amino]pentanedioic acid;

- [ [(3-trifluoromethylbenzyl)hydroxyphosphinyl]amino] pentanedioic acid;

- [ [(2-fluorobenzyl)hydroxyphosphinyl]amino]pentanedioic acid;

42. The use of claim 32, vvherein R_x or R₂ is heterocyclic and X is CH₂.

43. The use of claim 42, vvherein the NAALADase inhibitor is selected from the group consisting of:

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]pentanedioic acid; 2-[[(2-thienyl)hydroxyphosphinyl]methyl]pentanedioic acid; 2-[[(3-thienyl)hydroxyphosphinyl]methyl]pentanedioic acid;

2- [ [(4-thienyl)hydroxyphosphinyl]methyl]pentanedioic acid;

3- [(2-pyridyl)hydroxyphosphinyl]-2-phenylpropanoic acid;

3- [ (3-pyridyl)hydroxyphosphinyl]-2-phenylpropanoic acid;

3-[(4-pyridyl)hydroxyphosphinyl]-2-phenylpropanoic acid;

3-[(tetrahydrofuranyl)hydroxyphosphinyl]-2-phenylpropanoic acid;

3-[(2-indolyl)hydroxyphosphinyl]-2-phenylpropanoic acid;

3-[(3-indolyl)hydroxyphosphinyl]-2-phenylpropanoic acid;

3-[(4-indolyl)hydroxyphosphinyl]-2-phenylpropanoic acid ;

3-[(2-thienyl)hydroxyphosphinyl]-2-phenylpropanoic acid;

3- [ (3-thienyl)hydroxyphosphinyl]-2-phenylpropanoic acid;

3-[(4-thienyl)hydroxyphosphinyl]-2-phenylpropanoic acid;

3-(benzylhydroxyphosphinyl)-2-(2-pyridyl)propanoic acid;

3-(benzylhydroxyphosphinyl)-2-(3-pyridyl)propanoic acid;

3-(benzylhydroxyphosphinyl)-2-(4-pyridyl)propanoic acid;

3-(benzylhydroxyphosphinyl)-2-(tetrahydrofuranyl) propanoic acid;

3-(benzylhydroxyphosphinyl)-2-(2-indolyl)propanoic acid; 3-(benzylhydroxyphosphinyl)-2-(3-indolyl)propanoic acid; 3-(benzylhydroxyphosphinyl)-2-(4-indolyl)propanoic acid; 3-(benzylhydroxyphosphinyl)-2-(2-thienyl)propanoic acid; 3-(benzylhydroxyphosphinyl)-2-(3-thienyl)propanoic acid; 3-(benzylhydroxyphosphinyl)-2-(4-thienyl)propanoic acid; and a pharmaceutically acceptable salt, hydrate, or a mixture thereof.

44. The	use	of	claim	32,	vvherein		or R₂ is
heterocyclic	and	X is	oxygen.
45. The	use	of	claim	44,	vvherein	the	NAALADase

inhibitor is selected from the group consisting of: 2-[[(2-pyridyl)hydroxyphosphinyl]oxy]pentanedioic acid ;

2-[[(3-pyridyl)hydroxyphosphinyl]oxy]pentanedioic acid;

2-[[(4-pyridyl)hydroxyphosphinyl]oxy]pentanedioic acid;

- [ [(tetrahydrofuranyl)hydroxyphosphinyl]oxy]pentanedioic acid;

2-[[(2-indolyl)hydroxyphosphinyl]oxy]pentanedioic acid;

2-[[(3-indolyl)hydroxyphosphinyl]oxy]pentanedioic acid;

2-[[(4-indolyl)hydroxyphosphinyl]oxy]pentanedioic acid;

2-[[(2-thienyl)hydroxyphosphinyl]oxy]pentanedioic acid;

-[[(3 -thienyl)hydroxyphosphinyl]oxy]pentanedioic acid;

-[[(4-thienyl)hydroxyphosphinyl]oxy]pentanedioic acid;

2-[[(2-pyridyl)hydroxyphosphinyl]oxy]-2-phenylethanoic acid;

2-[[(3-pyridyl)hydroxyphosphinyl]oxy]-2-phenylethanoic acid;

2-[[(4-pyridyl)hydroxyphosphinyl]oxy]-2-phenylethanoic acid;

2-[[(tetrahydrofuranyl)hydroxyphosphinyl]oxy]-2-phenyl ethanoic acid;

2-[[(2-indolyl)hydroxyphosphinyl]oxy]-2-phenylethanoic acid;

2-[[(3-indolyl)hydroxyphosphinyl]oxy]- 2-phenylethanoic acid;

2-[[(4-indolyl)hydroxyphosphinyl]oxy]-2-phenylethanoic acid;

2-[[(2-thienyl)hydroxyphosphinyl]oxy]-2-phenylethanoic acid;

2-[[(3-thienyl)hydroxyphosphinyl]oxy]-2-phenylethanoic acid;

2-[[(4-thienyl)hydroxyphosphinyl]oxy]-2-phenylethanoic acid;

2-[[benzylhydroxyphosphinyl]oxy]-2-(2-pyridyl)ethanoic acid;

2-[[benzylhydroxyphosphinyl]oxy]-2-(3-pyridyl)ethanoic acid;

2-[[benzylhydroxyphosphinyl]oxy]-2-(4-pyridyl)ethanoic acid;

2-[[benzylhydroxyphosphinyl]oxy]-2-(tetrahydrofuranyl) ethanoic acid;

2-[[benzylhydroxyphosphinyl]oxy]-2-(2-indolyl)ethanoic acid;

2-[[benzylhydroxyphosphinyl]oxy]-2-(3-indolyl)ethanoic acid;

2-[[benzylhydroxyphosphinyl]oxy]-2-(4 -indolyl)ethanoic acid;

2-[[benzylhydroxyphosphinyl]oxy]-2-(2-thienyl)ethanoic acid;

2-[[benzylhydroxyphosphinyl]oxy]-2-(3-thienyl)ethanoic acid;

2-[[benzylhydroxyphosphinyl]oxy]-2-(4-thienyl)ethanoic acid; and a pharmaceutically acceptable salt, hydrate, or a

mixture thereof.
46. The	use	of	claim	32,	wherein	^R1	or R₂ is
heterocyclic	and	X is	νι\.
47. The	use	of	claim	46,	wherein	the	NAALADase
inhibitor is	a compound selected	from the	group	consisting

of :

2-[[(2-pyridyl)hydroxyphosphinyl]amino]pentanedioic acid; 2-[[(3-pyridyl)hydroxyphosphinyl]amino]pentanedioic acid; 2-[[4-pyridyl)hydroxyphosphinyl]amino]pentanedioic acid; 2-[[(tetrahydrofuranyl)hydroxyphosphinyl]amino] pentanedioic acid;

2-[[(2-indolyl)hydroxyphosphinyl]amino]pentanedioic acid; 2- [[(3-indolyl)hydroxyphosphinyl]amino]pentanedioic acid; 2-[[(4-indolyl)hydroxyphosphinyl]amino]pentanedioic acid; 2-[[(2-thienyl)hydroxyphosphinyl]amino]pentanedioic acid; 2-[[(3-thienyl)hydroxyphosphinyl]amino]pentanedioic acid; 2-[[(4-thienyl)hydroxyphosphinyl]amino]pentanedioic acid; 2- [ [(2-pyridyl)hydroxyphosphinyl]amino]-2-phenylethanoic acid;

2-[[(3-pyridyl)hydroxyphosphinyl]amino]-2-phenylethanoic acid;

2-[((4-pyridyl)hydroxyphosphinyl]amino]-2-phenylethanoic acid;

2-[[(tetrahydrofuranyl)hydroxyphosphinyl]amino]-2-phenyl ethanoic acid;

2-[[(2-indolyl)hydroxyphosphinyl]amino]-2-phenylethanoic acid;

2-[[(3-indolyl)hydroxyphosphinyl]amino]-2-phenylethanoic acid;

2-[[(4-indolyl)hydroxyphosphinyl]amino]-2-phenylethanoic acid;

2-[[(2-thienyl)hydroxyphosphinyl]amino]-2-phenylethanoic acid;

2-[[(3-thienyl)hydroxyphosphinyl]amino]-2-phenylethanoic acid;

2-[[(4-thienyl)hydroxyphosphinyl]amino]-2-phenylethanoic acid;

2- [ [benzylhydroxyphosphinyl]amino]-2-(2-pyridyl)ethanoic acid;

2-[[benzylhydroxyphosphinyl]amino]-2-(3-pyridyl)ethanoic acid;

2-[[benzylhydroxyphosphinyl]amino]-2-(4-pyridyl)ethanoic acid;

2- [ [benzylhydroxyphosphinyl]amino]-2-(tetrahydrofuranyl) ethanoic acid;

2-[[benzylhydroxyphosphinyl]amino]-2-(2-indolyl)ethanoic acid;

2-[[benzylhydroxyphosphinyl]amino]-2-(3-indolyl)ethanoic acid;

2- [ [benzylhydroxyphosphinyl]amino]-2-(4-indolyl)ethanoic acid;

2-[ [benzylhydroxyphosphinyl]amino]-2-(2-thienyl)ethanoic acid;

2-[[benzylhydroxyphosphinyl]amino]-2-(3-thienyl)ethanoic acid;

2-[[benzylhydroxyphosphinyl]amino] -2-(4-thienyl)ethanoic acid;

and a pharmaceutically acceptable salt, hydrate, or a mixture thereof.

48. Use of a NAALADase inhibitor for inhibiting NAALADase enzyme activity in an animal suffering from a disorder related to NAALADase enzyme activity.

49. The use of claim 48, vvherein the NAALADase inhibitor is selected from the group consisting of: a glutamate-derived hydroxyphosphinyl derivative compound; an acidic peptide analog; a conformationally restricted glutamate mimic; and mixtures thereof.

50. The use of claim 49, vvherein the NAALADase inhibitor is a glutamate-derived hydroxyphosphinyl derivative compound.

51. The use of claim 48, vvherein the NAALADase inhibitor is used in combination vvith an additional therapeutic aģent selected from the group consisting of: therapeutic hormones, chemotherapeutic hormones, antiangiogenesis aģents, radiolabelled compounds, and mixtures thereof.

52. The use of claim 48, vvherein the disorder related to NAALADase enzyme activity is prostate disease vvherein the prostate disease is selected from the group consisting of prostate cancer and benign prostatic hyperplasia.

53. The use of claim 48, vvherein the NAALADase inhibitor comprises a compound having the follovving formula:

O

Ri -ρχ

OH

R2

X^ ^COOH

Formula I, vvherein

R, is hydrogen, C₁-C_g straight or branched chain

C₂-C₉ straight or branched chain aikenyl alkyl, group, C₃-C₃ cycloalkyl, C₅-C₇ cycloalkenyl, or Ar₁; is CH₂, 0, or NR_X, vvhere R₂ is defined above; and

X

R₂ is C₁-C₉ straight or branched chain alkyl, C₂-C₉straight or branched chain alkenyl group, C₃-C_acycloalkyl, C₅-C₇ cycloalkenyl, or Ar_x, vvherein said alkyl, alkenyl, cycloalkyl, cycloalkenyl or aryl group may be optionally substituted vvith carboxylic acid, vvherein said alkyl, alkenyl, cycloalkyl, cycloalkenyl or aryl groups may be optionally substituted vvith C₃-C_acycloalkyl, C₃ or C₅ cycloalkyl, C₅-C₇ cycloalkenyl, C₁-C₄alkyl, ^c1^_c4 alkenyl, halo, hydroxy, carboxy, nitro, trifluoromethyl, C₁-C₆ straight or branched chain alkyl or alkenyl, C₃-C₄ alkoxy, C_x-C₄ alkenyloxy, phenoxy, benzyloxy, amino, or Ar_lZ and vvhere Ar_x is selected from the group consisting of l-naphthyl, 2-naphthyl, 2-indolyl, 3-indolyl, 4-indolyl, 2-furyl, 3-furyl, tetrahydrofuranyl, 2-thienyl, 3-thienyl, 4-thienyl, 2-,3-, or 4-pyridyl, or phenyl, having one to five substituents vvhich are independently selected from the group consisting of hydrogen, halo, hydroxy, carboxy, nitro, trifluoromethyl, C₁-C₆ straight or branched alkyl or alkenyl, C_x-C₄ alkoxy or C₁-C₄ alkenyloxy, pnenoxy, benzyloxy, and amino; or pharmaceutically acceptable salts, hydrates, or mixtures thereof.

54. The use of claim 53, vvherein R and R₂ are straight or branched aliphacic groups or carbocyclic groups and X is ch₂.

55. The use of claim 54, vvherein the NAALADaseinhibitor is selected from the group consisting of:

2-[[methylhydroxyphosphinyl]methyl]pentanedioic acid;

2-[[ethylhydroxyphosphinyl]methyl]pentanedioic acid;

2-[[propylhydroxyphosphinyl]methyl]pentanedioic acid;

2-[[butylhydroxyphosphinyl]methyl]pentanedioic acid;

2-[[cyclohexylhydroxyphosphinyl]methyl]pentanedioic acid;

2-[[(cyclohexyl)methylhydroxyphosphinyl]methyl] pentanedioic acid;

2-[[phenylhydroxyphosphinyl]methyl]pentanedioic acid;

2-[[benzylhydroxyphosphinyl]methyl]pentanedioic acid;

2-[[phenylethylhydroxyphosphinyl]methyl]pentanedioic acid; 2-[[phenylpropylhydroxyphosphinyl]methyl]pentanedioic acid; 2-[[phenylbutylhydroxyphosphinyl]methyl]pentanedioic acid; 2-[[(4-methylbenzyl)hydroxyphosphinyl]methyl]pentanedioic acid;

- [ [(4-fluorobenzyl)hydroxyphosphinyl]methyl]pentanedioic acid;

- [ ( (2-f luorobenzyl) hydroxyphosphinyl] methyl] pentanedioic acid;

2-[[(pentafluorobenzyl)hydroxyphosphinyl]methyl] pentanedioic acid;

2-[[(methoxybenzyl)hydroxyphosphinyl]methyl]pentanedioic acid;

2-[[(2,3,4-trimethoxyphenyl)hydroxyphosphinyl]methyl] pentanedioic acid;

2-[[(l-naphthyl)hydroxyphosphinyl]methyl]pentanedioic acid; 2-[[(2-naphthyl)hydroxyphosphinyl]methyl]pentanedioic acid; 2-[((l-naphthyl)methylhydroxyphosphinyl]methyl] pentanedioic acid;

2- [ [(2-naphthyl)methylhydroxyphosphinyl]methyl] pentanedioic acid;

2-[[(l-naphthyl)ethylhydroxyphosphinyl]methyl]pentanedioic acid;

- [ [(2-naphthyl)ethylhydroxyphosphinyl]methyl]pentanedioic acid;

2-[[(l-naphthyl)propylhydroxyphosphinyl]methyl] pentanedioic acid;

-[[(2-naphthyl)propylhydroxyphosphinyl]methyl] pentanedioic acid;

2-[[(l-naphthyl)butylhydroxyphosphinyl]methyl]pentanedioic acid;

2-[[(2-naphthyl)butylhydroxyphosphinyl]methyl]pentanedioic acid;

2- [ [ (phenylprop-2-enyl)hydroxyphosphinyl]methyl] pentanedioic acid;

2-[[(2-fluorobenzyl)hydroxyphosphinyl]methyl]pentanedioic acid;

2- [ [(4-fluorophenyl)hydroxyphosphinyl]methyl]pentanedioic acid;

-[[((hydroxy)phenylmethyl)hydroxyphosphinyl]methyl] pentanedioic acid;

— [ [(3-methylbenzyl)hydroxyphosphinyl]methyl]pentanedioic acid;

2-(phosphonomethyl)pentanedioic acid;

2- [ [ (3-trifluoromethylbenzyl)hydroxyphosphinyl]methyl] pentanedioic acid;

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-(beņzylhydroxyphosphinyl)-2-phenylpropanoic acid;

3-(phenylethylhydroxyphosphinyl)-2-phenylpropanoic acid;

3-(phenylpropylhydroxyphosphinyl)-2-phenylpropanoic acid; 3-(phenylbutylhydroxyphosphinyl)-2-phenylpropanoic acid;

3-((2,3,4 -trimethoxyphenyl)-3-hydroxyphosphinyl)-2phenylpropanoic acid;

3- ( (l-naphthyl) hydroxyphosphinyl) -2-phen.ylpropan.oic acid; 3-((2-naphthyl)hydroxyphosphinyl)-2-phenylpropanoic acid; 3-((l-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-((l-naphthyl)propylhydroxyphosphinyl)-2-phenylpropanoic acid;

3-((2-naphthyl)propylhydroxyphosphinyl)-2-phenylpropanoic acid;

3-((l-naphthyl)butylhydroxyphosphinyl)-2-phenylpropanoic acid;

3-((2-naphthyl)butylhydroxyphosphinyl)-2-phenylpropanoic acid;

3-(phenylprop-2-enylhydroxyphosphinyl)-2-phenylpropanoic acid;

2-[(benzylhydroxyphosphinyl)methyl]pentanedioic acid;

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]octanedioic acid;

-[(methylhydroxyphosphinyl)methyl]nonanedioic acid;

2-[(benzylhydroxyphosphinyl)methyl]nonanedioic acid;

2-[(methylhydroxyphosphinyl)methyl]decanedioic acid;

2- [(benzylhydroxyphosphinyl)methyl]decanedioic acid;

3- (benzylhydroxyphosphinyl)-2-methylpropanoic acid;

3-(benzylhydroxyphosphinyl)-2-ethylpropanoic acid;

3-(benzylhydroxyphosphinyl)-2-propylpropanoic acid;

3-(benzylhydroxyphosphinyl)-2-butylpropanoic acid;

3-(benzylhydroxyphosphinyl)-2-cyclohexylpropanoic acid;

3-(benzylhydroxyphosphinyl)-2-(cyclohexyl)methylpropanoic acid;

3-(benzylhydroxyphosphinyl)-2-phenylpropanoic acid;

3-(benzylhydroxyphosphinyl)-2-benzylpropanoic acid;

3-(benzylhydroxyphosphinyl)-2-phenylethylpropanoic acid; 3-(benzylhydroxyphosphinyl)-2-phenylpropylpropanoic acid; 3-(benzylhydroxyphosphinyl)-2-phenylbutylpropanoic acid; 3-(benzylhydroxyphosphinyl)-2-(2,3,4-trimethoxyphenyl) propanoic acid;

3-(benzylhydroxyphosphinyl)-2-(2-naphthyl)methylpropanoic acid;

3-(benzylhydroxyphosphinyl)-2-(l-naphthyl)ethylpropanoic acid;

3-(benzylhydroxyphosphinyl)-2-(2-naphthyl)ethylpropanoic acid;

3-(benzylhydroxyphosphinyl)-2-(l-naphthyl)propylpropanoic acid;

3-(benzylhydroxyphosphinyl)-2-(2-naphthyl)propylpropanoic acid;

3-(benzylhydroxyphosphinyl)-2-(1-naphthyl)butylpropanoic acid;

3-(benzylhydroxyphosphinyl)-2-(2-naphthyl)butylpropanoic acid;

3-(benzylhydroxyphosphinyl)-2-phenylprop-2-enylpropanoic acid;

2-[((2-pyridyl)methylhydroxyphosphinyl]methyl]pentanedioic acid;

- [ [ (3-pyridyl)methylhydroxyphosphinyl]methyl]pentanedioic acid;

2-[[(4-pyridyl)methylhydroxyphosphinyl]methyl]pentanedioic acid;

2- [ [ (3-pyridyl)ethylhydroxyphosphinyl]methyl]pentanedioic acid;

- [ [ (3-pyridyl)propylhydroxyphosphinyl]methyl]pentanedioic acid;

2-[[(tetrahydrofuranyl)methylhydroxyphosphinyl]methyl] pentanedioic acid;

- [ [ (tetrahydrofuranyl)ethylhydroxyphosphinyl]methyl] pentanedioic acid;

2-[[(tetrahydrofuranyl)propylhydroxyphosphinyl]methyl] pentanedioic acid;

-[[(2 -indolyl)methylhydroxyphosphinyl]methyl]pentanedioic acid;

2- [ [(3-indolyl)methylhydroxyphosphinyl]methyl]pentanedioic acid;

2- [ [ (4 -indolyl)methylhydroxyphosphinyl]methyl]pentanedioic acid;

- [ [ (3-indoiyl)ethylhydroxyphosphinyl]methyl]pentanedioic acid;

2-[[(3-indolvl)propylhydroxyphosphinyl]methyl]pentanedioic acid;

- [ [(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;

-[[(3-thienyl)propylhydroxyphosphinyl]methyl]pentanedioic acid;

3- [(2-pyridyl)methylhydroxyphosphinyl]-2-phenylpropanoic acid;

3-[(3-pyridyl)methylhydroxyphosphinyl]-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-phenyl propanoic acid;

3-[(tetrahydrofuranyl)ethylhydroxyphosphinyl]-2-phenyl propanoic acid;

3-[(tetrahydrofuranyl)propylhydroxyphosphinyl]-2phenyl propanoic 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-phenylpropanoic acid;

3-(benzylhydroxyphosphinyl)-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-(tetrahydrofuranyl)methyl propanoic acid;

3-(benzylhydroxyphosphinyl)-2-(tetrahydrofuranyl)ethyl propanoic acid;

3-(benzylhydroxyphosphinyl)-2-(tetrahydrofuranyl)propyl propanoic 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)ethylpropanoic 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;

56. The use of claim 54, vvherein the NAALADase inhibitor is selected from the group consisting of:

2-[(benzylhydroxyphosphinyl)methyl]pentanedioic acid;

2-[(phenylhydroxyphosphinyl)methyl]pentanedioic acid;

-[[((hydroxy)phenylmethyl)hydroxyphosphinyl]methyl] pentanedioic acid;

2-[(butylhydroxyphosphinyl)methyl]pentanedioic acid;

2-[[(3-methylbenzyl)hydroxyphosphinyl]methyl]pentanedioic acid;

2-[(3-phenylpropylhydroxyphosphinyl)methyl]pentanedioic acid;

-[[(4-fluorophenyl)hydroxyphosphinyl]methyl]pentanedioic acid;

2-[(methylhydroxyphosphinyl)methyl]pentanedioic acid;

2-[(phehylethylhydroxyphosphinyl)methyl]pentanedioic acid; 2-[[(4-methylbenzyl)hydroxyphosphinyl]methyl]pentanedioic acid;

2- [ [ (4-fluorobenzyl) hydroxyphosphinyl] methyl] pentanedioic acid;

- [ [(4-methoxybenzyl)hydroxyphosphinyl]methyl] pentanedioic acid;

2-(phosphonomethyl)pentanedioic acid;

2-[[(3-trifluoromethylbenzyl)hydroxyphosphinyl]methyl] pentanedioic acid;

- [ [ (2-fluorobenzyl)hydroxyphosphinyl]methyl]pentanedioic acid;

57. The use of claim 53 vvherein R_x and R₂ are straight or branched aliphatic groups or carbocyclic groups and X is oxygen.

58. The use of claim 57 vvherein the NAALADase inhibitor is selected from the group consisting of:

2- [ [methylhydroxyphosphinyl]oxy]pentanedioic acid;

2-[[ethylhydroxyphosphinyl]oxy]pentanedioic acid;

- [ [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;

-[[phenylethylhydroxyphosphinyl]oxy]pentanedioic acid;

2- [ [phenylpropylhydroxyphosphinyl]oxy]pentanedioic acid;

- [ [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;

- [ [(pentafluorobenzyl)hydroxyphosphinyl]oxy]pentanedioic acid;

2-[[(methoxybenzyl)hydroxyphosphinyl]oxy]pentanedioic acid; 2 -[[(2,3,4 -trimethoxyphenyl)hydroxyphosphinyl]oxy] pentanedioic acid;

2-[[(l-naphthyl)hydroxyphosphinyl]oxy]pentanedioic acid;

2-[[(2-naphthyl)hydroxyphosphinyl]oxy]pentanedioic acid;

2-[[(l-naphthyl)methylhydroxyphosphinyl]oxy]pentanedioic acid;

2-[[(2-naphthyl)methylhydroxyphosphinyl]oxy]pentanedioic acid;

2-[[(l-naphthyl)ethylhydroxyphosphinyl]oxy]pentanedioic acid;

2-[[(2-naphthyl)ethylhydroxyphosphinyl]oxy]pentanedioic acid;

2-[[(l-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-[[(4-fluorophenyl)hydroxyphosphinyl]oxy]pentanedioic acid;

2-[[((hydroxy)phenylmethyl)hydroxyphosphinyl]oxy] pentanedioic acid;

2-[[(3-methylbenzyl)hydroxyphosphinyl]oxy]pentanedioic acid;

2- [ (phosphono)oxy]pentanedioic acid;

2-[[(3-trifluoromethylbenzyl)hydroxyphosphinyl]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-phenylethanoic acid;

2- [ [cyclohexylhydroxyphosphinyl]oxy]-2-phenylethanoic acid; 2-[[(cyclohexyl)methylhydroxyphosphinyl]oxy]-2phenylethanoic acid;

2- [ [phenylhydroxyphosphinyl]oxy]-2-phenylethanoic acid;

2-[[benzylhydroxyphosphinyl]oxy]-2-phenylethanoic acid;

2-[[phenylethylhydroxyphosphinyl]oxy]-2-phenylethanoic acid;

2-[[phenylpropylhydroxyphosphinyl]oxy]-2-phenylethanoic acid;

2-[[phenylbutylhydroxyphosphinyl]oxy]-2-phenylethanoic acid;

2-[[(2,3,4-trimethoxyphenyl)-3-hydroxyphosphinyl]oxy]-2phenylethanoic acid;

2- [ [(2-naphthyl)hydroxyphosphinyl]oxy]-2-phenylethanoic acid;

2-[[(3-naphthyl)hydroxyphosphinyl]oxy]-2-phenylethanoic acid;

2-[[(4-naphthyl)hydroxyphosphinyl]oxy]-2-phenylethanoic acid;

- [ [ (2-naphthyl)methylhydroxyphosphinyl)]oxy]-2-phenyl ethanoic acid;

2-[[(3-naphthyl)methylhydroxyphosphinyl]oxy]-2-phenyl ethanoic acid;

2-[[(4-naphthyl)methylhydroxyphosphinyl]oxy]-2-phenyl ethanoic acid;

2-[[(3-naphthyl)ethylhydroxyphosphinyl]oxy]-2-phenyl ethanoic acid;

2-[[(3-naphthyl)propylhydroxyphosphinyl]oxy]-2-phenyl ethanoic acid;

2-[[(3-naphthyl)butylhydroxyphosphinyl]oxy]-2-phenyl ethanoic acid;

2-[[phenylprop-2-enylhydroxyphosphinyl]oxy]-2-phenyl ethanoic acid;

2-[(methylhydroxyphosphinyl)oxy]hexanedioic acid;

-[(benzylhydroxyphosphinyl)oxy]hexanedioic acid;

2-[(methylhydroxyphosphinyl)oxy]heptanedioic acid;

2-[(benzylhydroxyphosphinyl)oxy]heptanedioic acid;

2-[(methylhydroxyphosphinyl)oxy]octanedioic acid;

2-[(benzylhydroxyphosphinyl)oxy]octanedioic acid;

-[(methylhydroxyphosphinyl)oxy]nonanedioic acid;

2-[(benzylhydroxyphosphinyl)oxy]nonanedioic acid;

2-[(methylhydroxyphosphinyl)oxy]decanedioic acid;

2- [ (benzylhydroxyphosphinyl)oxy]decanedioic acid;

2-[[benzylhydroxyphosphinyl]oxy]-2-methylethanoic acid;

2-[[benzylhydroxyphosphinyl]oxy]-2-ethylethanoic acid;

2- [ [benzylhydroxyphosphinyl]oxy]-2-propylethanoic acid;

2- [ [benzylhydroxyphosphinyl]oxy]-2-butylethanoic acid;

2-[[benzylhydroxyphosphinyl]oxy]-2-cyclohexylethanoic acid; 2-[[benzylhydroxyphosphinyl]oxy]-2-(cyclohexyl)methyl ethanoic acid;

2- [ [benzylhydroxyphosphinyl]oxy]-2-phenylethanoic acid;

2-[[benzylhydroxyphosphinyl]oxy]-2-benzylethanoic acid;

2-[[benzylhydroxyphosphinyl]oxy]-2-phenylethylethanoic acid;

2-[[benzylhydroxyphosphinyl]oxy]-2-phenylpropylethanoic acid;

2-[[benzylhydroxyphosphinyl]oxy]-2-phenylbutylethanoic acid;

2- [ [benzylhydroxyphosphinyl]oxy]-2-(2,3,4 -trimethoxyphenyl) ethanoic acid;

2-[[benzylhydroxyphosphinyl]oxy]-2-(l-naphthyl)ethanoic acid;

2- [ [benzylhydroxyphosphinyl]oxy]-2-(2-naphthyl)ethanoic acid;

2-[[benzylhydroxyphosphinyl]oxy]-2-(l-naphthyl)methyl ethanoic acid;

2-[[benzylhydroxyphosphinyl]oxy]-2-(2-naphthyl)methyl ethanoic acid;

2-[[benzylhydroxyphosphinyl]oxy]-2-(l-naphthyl)ethyl ethanoic acid;

2-[[benzylhydroxyphosphinyl]oxy]-2-(2-naphthyl)ethyl ethanoic acid;

2-[[benzylhydroxyphosphinyl]oxy]-2-(l-naphthyl)propyl ethanoic acid;

2-[[benzylhydroxyphosphinyl]oxy]-2-(2-naphthyl)propyl ethanoic acid;

2-[[benzylhydroxyphosphinyl]oxy]-2-(l-naphthyl)butyl ethanoic acid;

2-[[benzylhydroxyphosphinyl]oxy]-2-(2-naphthyl)butyl ethanoic acid;

2-[[benzylhydroxyphosphinyl]oxy]-2-phenylprop-2enylethanoic acid;

2-[[(2-pyridyl)methylhydroxyphosphinyl]oxy]pentanedioic acid;

2-[[(3-pyridyl)methylhydroxyphosphinyl]oxy]pentanedioic acid;

- [ [(4-pyridyl)methylhydroxyphosphinyl]oxy]pentanedioic acid;

- [ [(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)propylhydroxyphosphinyl]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]pentanedioic acid;

2-[[(2-thienyl)methylhydroxyphosphinyl]oxy]pentanedioic acid;

2-[[(3-thienyl)methylhydroxyphosphinyl]oxy]pentanedioic acid;

2-[[(4-thienyl)methylhydroxyphosphinyl]oxy]pentanedioic acid;

-[[(3-thienyl)ethylhydroxyphosphinyl]oxy]pentanedioic acid;

2-[[(3-thienyl)propylhydroxyphosphinyl]oxy]pentanedioic acid;

2-[[(2-pyridyl)methylhydroxyphosphinyl]oxy]-2-phenyl ethanoic acid;

2-[[(3-pyridyl)methylhydroxyphosphinyl]oxy]-2-phenyl ethanoic acid;

2-[[(4-pyridyl)methylhydroxyphosphinyl]oxy]-2-phenyl ethanoic acid;

2-[[(3-pyridyl)ethylhydroxyphosphinyl]oxy]-2-phenyl ethanoic acid;

2-[[(3-pyridyl)propylhydroxyphosphinyl]oxy]-2-phenyl ethanoic acid;

2-[[(tetrahydrofuranyl)methylhydroxyphosphinyl]oxy]-2phenylethanoic acid;

-[[(tetrahydrofuranyl)ethylhydroxyphosphinyl]oxy]-2phenylethanoic acid;

2-[[(tetrahydrofuranyl)propylhydroxyphosphinyl]oxy]-2phenylethanoic acid;

2-[[(2-indolyl)methylhydroxyphosphinyl]oxy]-2-phenyl ethanoic acid;

2-[[(3-indolyl)methylhydroxyphosphinyl]oxy]-2-phenyl ethanoic acid;

2-[[(4-indolyl)methylhydroxyphosphinyl]oxy]-2-phenyl ethanoic acid;

2-[[(3-indolyl)ethylhydroxyphosphinyl]oxy]-2-phenyl ethanoic acid;

2-[[(3-indolyl)propylhydroxyphosphinyl]oxy]-2-phenyl ethanoic acid;

2-[[(2-thienyl)methylhydroxyphosphinyl]oxy]-2-phenyl ethanoic acid;

2-[[(3-thienyl)methylhydroxyphosphinyl]oxy]-2-phenyl ethanoic acid;

2-[[(4-thienyl)methylhydroxyphosphinyl]oxy]-2-phenyl ethanoic acid;

2-[[(3-thienyl)ethylhydroxyphosphinyl]oxy]-2-phenyl ethanoic acid;

2-[[(3 -thienyl)propylhydroxyphosphinyl]oxy]-2-phenyl ethanoic acid;

2-[[benzylhydroxyphosphinyl]oxy]-2-(2-pyridyl)methyl ethanoic acid;

2-[[benzylhydroxyphosphinyl]oxy]-2-(3-pyridyl)methyl ethanoic acid;

2-[[benzylhydroxyphosphinyl]oxy]-2-(4-pyridyl)methyl ethanoic acid;

2-[[benzylhydroxyphosphinyl]oxy]-2-(3-pyridyl)ethyl ethanoic acid;

2-[[benzylhydroxyphosphinyl]oxy]-2-(3-pyridyl)propyl ethanoic acid;

2-[[benzylhydroxyphosphinyl]oxy]-2-(tetrahydrafuranyl) methylethanoic acid;

2-[[benzylhydroxyphosphinyl]oxy]-2-(tetrahydrafuranyl) ethylethanoic acid;

2-[[benzylhydroxyphosphinyl]oxy]-2-(tetrahydrafuranyl) propylethanoic acid;

2-[[benzylhydroxyphosphinyl]oxy]-2-(2-indolyl) methylethanoic acid;

2-[[benzylhydroxyphosphinyl]oxy]-2-(3 -indolyl)methyl ethanoic acid;

2-[[benzylhydroxyphosphinyl]oxy]-2-(4-indolyl)methyl ethanoic acid;

2-[[benzylhydroxyphosphinyl]oxy]-2-(3-indolyl)ethyl ethanoic acid;

2-[[benzylhydroxyphosphinyl]oxy]-2-(3-indolyl)propyl ethanoic acid;

2-[[benzylhydroxyphosphinyl]oxy]-2-(2-thienyl)methyl ethanoic acid;

2- [ [benzylhydroxyphosphinyl]oxy]-2-(3-thienyl)methyl ethanoic acid;

2-([benzylhydroxyphosphinyl]oxy]-2-(4-thienyl)methyl ethanoic acid;

2-[[benzylhydroxyphosphinyl]oxy]-2-(3-thienyl)ethyl ethanoic acid;

2- [ [benzylhydroxyphosphinyl]oxy]-2-(3-thienyl) propylethanoic acid; and a pharmaceutically acceptable salt, hydrate, or a mixture thereof.

59. The use of claim 57, vvherein the NAALADase inhibitor is selected from the group consisting of:

2- [ (benzylhydroxyphosphinyl)oxy]pentanedioic acid;

2-[(phenylhydroxyphosphinyl)oxy]pentanedioic acid;

2-[[((hydroxy)phenylmethyl)hydroxyphosphinyl]oxy] pentanedioic acid;

2-[(butylhydroxyphosphinyl)oxy]pentanedioic acid;

- [ [ (3-methylbenzyl)hydroxyphosphinyl]oxy]pentanedioic acid;

2- [ (3-phenylpropylhydroxyphosphinyl)oxy]pentanedioic acid; 2- [ [ (4-fluorophenyl)hydroxyphosphinyl]oxy]pentanedioic acid;

2-[(methylhydroxyphosphinyl)oxy]pentanedioic acid;

2-[(phenylethylhydroxyphosphinyl)oxy]pentanedioic acid;

-[[(4-methylbenzyl)hydroxyphosphinyl]oxy]pentanedioic acid;

- [ [ (4-fluorobenzyl)hydroxyphosphinyl]oxy]pentanedioic acid;

2-[[(4-methoxybenzyl)hydroxyphosphinyl]oxy]pentanedioic acid;

- [ [ (2-fluorobenzyl)hydroxyphosphinyl]oxy]pentanedioic acid;

2-[[(pentafluorobenzyl)hydroxyphosphinyl]oxy]pentanedioic acid;

2-[(phosphono)oxy]pentanedioic acid;

2- [ [(3-trifluoromethylbenzyl)hydroxyphosphinyl]oxy] pentanedioic acid; and a pharmaceutically acceptable salt, hydrate, or a mixture thereof.

60. The use of claim 53, wherein R_x and R₂ are straight or branched aliphatic groups or carbocyclic and X is NR .

61. The use of claim 60, wherein che NAALADase inhibitor is selecced from the group consisting of:

2- [ [methylhydroxyphosphinyl]amino]pentanedioic acid;

2-[[ethylhydroxyphosphinyl]amino]pentanedioic acid;

2-[[propylhydroxyphosphinyl]amino]pentanedioic acid;

2- [ [butylhydroxyphosphinyl]amino]pentanedioic acid;

2- [ [cyclohexylhydroxyphosphinyl]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]pentanedioic acid;

2-[[(4-methylbenzyl)hydroxyphosphinyl]amino]pentanedioic acid;

2- [ [(4-fluorobenzyl)hydroxyphosphinyl]amino]pentanedioic acid;

2-[[(2-fluorobenzyl)hydroxyphosphinyl]amino]pentanedioic acid;

2-[[(pentafluorobenzyl)hydroxyphosphinyl]amino] pentanedioic acid;

2-[[(methoxybenzyl)hydroxyphosphinyl]amino]pentanedioic acid;

2- [ [ (2,3,4-trimethoxyphenyl)hydroxyphosphinyl]amino] pentanedioic acid;

2-[[(l-naphthyl)hydroxyphosphinyl]amino]pentanedioic acid; 2-[[(2-naphthyl)hydroxyphosphinyl]amino]pentanedioic acid; 2 - [ [(l-naphthyl)methylhydroxyphosphinyl]amino] pentanedioic acid;

2-[[(2-naphthyl)methylhydroxyphosphinyl]amino]pentanedioic acid;

2-[[(l-naphthyl)ethylhydroxyphosphinyl]amino]pentanedioic acid;

2- [ ((2-naphthyl)ethylhydroxyphosphinyl]amino]pentanedioic acid;

2-[[(l-naphthyl)propylhydroxyphosphinyl]amino]pentanedioic acid;

- [ [(2-naphthyl)propylhydroxyphosphinyl]amino] pentanedioic acid;

2-[[(l-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-[[(4-fluorophenyl)hydroxyphosphinyl]amino]pentanedioic acid;

2- [ [ ((hydroxy)phenylmethyl)hydroxyphosphinyl]amino] pentanedioic acid;

-[[(3-methylbenzyl)hydroxyphosphinyl]amino]pentanedioic acid;

2- [ (phosphono)amino]pentanedioic acid;

2-[[(3-trifluoromethylbenzyl)hydroxyphosphinyl]amino] pentanedioic acid;

2-[[cyclohexylhydroxyphosphinyl]amino]-2-phenylethanoic acid;

2-[[(cyclohexyl)methylhydroxyphosphinyl]amino]-2-phenyl ethanoic acid;

2-[[phenylpropylhydroxyphosphinyl]ammo]-2-phenylethanoic acid;

2-[[phenylbutylhydroxyphosphinyl]amino]-2-phenylethanoic acid;

2-[[(2,3,4-trimethoxyphenyl)-3-hydroxyphosphinyl]amino]-2phenylethanoic acid;

-[[(l-naphthyl)hydroxyphosphinyl]amino]-2-phenylethanoic acid;

2-[[(2-naphthyl)hydroxyphosphinyl]amino]-2-phenylethanoic acid;

2-[[(l-naphthyl)methylhydroxyphosphinyl)]amino]-2-phenyl ethanoic acid;

2-[[(2-naphthyl)methylhydroxyphosphinyl]amino]-2-phenyl ethanoic acid;

2-[[(l-naphthyl)ethylhydroxyphosphinyl]amino]-2-phenyl ethanoic acid;

2-[[(2-naphthyl)ethylhydroxyphosphinyl]amino]-2-phenyl ethanoic acid;

- [ [(l-naphthyl)propylhydroxyphosphinyl]amino]-2-phenyl ethanoic acid;

2-[[(2-naphthyl)propylhydroxyphosphinyl]amino] -2-phenyl ethanoic acid;

2-[[(l-naphthyl)butylhydroxyphosphinyl]amino]-2-phenyl ethanoic acid;

2-[[(2-naphthyl)butylhydroxyphosphinyl]amino]-2-phenyl ethanoic acid;

2-[[phenylprop-2-enylhydroxyphosphinyl]amino]-2-phenyl ethanoic acid;

2-[[benzylhydroxyphosphinyl]amino]-2-methylethanoic acid; 2- [ [benzylhydroxyphosphinyl]amino]-2-ethylethanoic acid; 2- [ [benzylhydroxyphosphinyl]amino]-2-propylethanoic acid; 2-[[benzylhydroxyphosphinyl]amino]-2-butylethanoic acid; 2-[[benzylhydroxyphosphinyl]amino]-2-cyclohexylethanoic acid;

2-[[benzylhydroxyphosphinyl]amino]-2-(cyclohexyl)methyl ethanoic acid;

2-[[benzylhydroxyphosphinyl]amino]-2-phenylpropylethanoic acid;

2-[[benzylhydroxyphosphinyl]amino]-2-phenylbutylethanoic acid;

2- [ [benzylhydroxyphosphinyl]amino]-2-(2,3,4trimethoxyphenyl)ethanoic acid;

2-[[benzylhydroxyphosphinyl]amino]-2-(l-naphthyl)ethanoic acid;

2-[[benzylhydroxyphosphinyl]amino]-2-(2-naphthyl)ethanoic acid;

2-[[benzylhydroxyphosphinyl]amino]-2-(l-naphthyl)methyl ethanoic acid;

2-[[benzylhydroxyphosphinyl]amino]-2-(2-naphthyl)methyl ethanoic acid;

2-[[benzylhydroxyphosphinyl]amino]-2-(l-naphthyl)ethyl ethanoic acid;

2-[[benzylhydroxyphosphinyl]amino]-2-(2-naphthyl)ethyl ethanoic acid;

2- [ [benzylhydroxyphosphinyl]amino]-2-(1-naphthyl)propyl ethanoic acid;

2-[[benzylhydroxyphosphinyl]amino]-2-(2-naphthyl)propyl ethanoic acid;

2-[[benzylhydroxyphosphinyl]amino]-2-(l-naphthyl)butyl ethanoic acid;

2-[[benzylhydroxyphosphinyl]amino]-2-(2-naphthyl)butyl ethanoic acid;

2-[[benzylhydroxyphosphinyl]amino]-2-phenolprop-2-enyl ethanoic 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]nonanedioic acid;

2-[(benzylhydroxyphosphinyl)amino]nonanedioic acid;

2-[(methylhydroxyphosphinyl)amino]decanedioic acid;

2- [(benzylhydroxyphosphinyl)amino]decanedioic acid;

-[[(2-pyridyl)methylhydroxyphosphinyl]amino]pentanedioic acid;

3- [[(3-pyridyl)methylhydroxyphosphinyl]amino]pentanedioic acid;

- [ [(4-pyridyl)methylhydroxyphosphinyl]amino]pentanedioic acid;

3-[[(3-pyridyl)ethylhydroxyphosphinyl]amino]pentanedioic acid;

3-[[(3-pyridyl)propylhydroxyphosphinyl]amino]pentanedioic acid;

—[[(tetrahydrofuranyl)methylhydroxyphosphinyl]amino] pentanedioic acid;

3-[[(tetrahydrofuranyl)ethylhydroxyphosphinyl]amino] pentanedioic acid;

3-[[(tetrahydrofuranyl)propylhydroxyphosphinyl]amino] pentanedioic acid;

-[[(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-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-thienyl)ethylhydroxyphosphinyl]amino]pentanedioic acid;

-[[(3-thienyl)propylhydroxyphosphinyl]amino]pentanedioic acid;

-[[(2-pyridyl)methylhydroxyphosphinyl]amino]-2-phenyl ethanoic acid;

2-[[(3-pyridyl)methylhydroxyphosphinyl]amino]-2-phenyl ethanoic acid;

2-[[(4-pyridyl)methylhydroxyphosphinyl]amino]-2-phenyl ethanoic acid;

2-[[(3-pyridyl)ethylhydroxyphosphinyl]amino]-2-phenyl ethanoic acid;

2-[((3-pyridyl)propylhydroxyphosphinyl]amino]-2-phenyl ethanoic acid;

2-[[(tetrahydrofuranyl)methylhydroxyphosphinyl]amino]-2phenylethanoic acid;

2-[[(tetrahydrofuranyl)ethylhydroxyphosphinyl] amino]-2phenylethanoic acid;

2-[[(tetrahydrofuranyl)propylhydroxyphosphinyl]amino]-2phenylethanoic acid;

2-[[(2-indolyl)methylhydroxyphosphinyl]amino]-2-phenyl ethanoic acid;

2-[[(3-indolyl)methylhydroxyphosphinyl]amino]-2-phenyl ethanoic acid;

2-[[(4-indolyl)methylhydroxyphosphinyl] amino] -2-phenyl ethanoic acid;

2-[[(3-indolyl)ethylhydroxyphosphinyl]amino]-2-phenyl ethanoic acid;

2-[[(3-indolyl)propylhydroxyphosphinyl]amino]-2-phenyl ethanoic acid;

2-[[(2-thienyl)methylhydroxyphosphinyl]amino]-2-phenyl ethanoic acid;

2-[[(3-thienyl)methylhydroxyphosphinyl]amino]-2-phenyl ethanoic acid;

2-[[(4-thienyl)methylhydroxyphosphinyl]amino]-2phenylethanoic acid;

2-[[(3-thienyl)ethylhydroxyphosphinyl]amino]-2phenylethanoic acid;

2-[[(3-thienyl)propylhydroxyphosphinyl]amino]-2phenylethanoic acid;

2-[[benzylhydroxyphosphinyl]amino]-2-(2-pyridyl)methyl ethanoic acid;

2- [ [benzylhydroxyphosphinyl]amino]-2-(3-pyridyl)methyl ethanoic acid;

2-[[benzylhydroxyphosphinyl]amino]-2-(4-pyridyl)methyl ethanoic acid;

2-[[benzylhydroxyphosphinyl)amino]-2-(3-pyridyl)ethyl ethanoic acid;

2-[[benzylhydroxyphosphinyl]amino]-2-(3-pyridyl)propyl ethanoic acid;

2-[[benzylhydroxyphosphinyl]amino]-2-(tetrahydrafuranyl) methylethanoic acid;

2-[[benzylhydroxyphosphinyl]amino]-2-(tetrahydrafuranyl) ethylethanoic acid;

2-[[benzylhydroxyphosphinyl]amino]-2-(tetrahydrafuranyl) propylethanoic acid;

2-[[benzylhydroxyphosphinyl]amino]-2-(2-indolyl)methyl ethanoic acid;

2-[[benzylhydroxyphosphinyl]amino]-2-(3-indolyl)methyl ethanoic acid;

2-[[benzylhydroxyphosphinyl]amino]-2-(4-indolyl)methyl ethanoic acid;

2-[[benzylhydroxyphosphinyl]amino]-2-(3 -indolyl)ethyl ethanoic acid;

2-[[benzylhydroxyphosphinyl]amino]-2-(3-indolyl)propyl ethanoic acid;

2-[[benzylhydroxyphosphinyl]amino]-2-(2-thienyl)methyl ethanoic acid;

2-[[benzylhydroxyphosphinyl]amino]-2-(3-thienyl)methyl ethanoic acid;

2-[[benzylhydroxyphosphinyl]amino]-2-(4-thienyl)methyl ethanoic acid;

2-[[benzylhydroxyphosphinyl]amino]-2-(3-thienyl)ethyl ethanoic acid;

2- [ [benzylhydroxyphosphinyl]amino]-2-(3 -thienyl)propyl ethanoic acid; and a pharmaceutically acceptable salt, hydrate, or a mixture thereof.

62. The use of claim 60, vvherein the NAALADase inhibitor is selected from the group consisting of:

2-[(benzylhydroxyphosphinyl)amino]pentanedioic acid;

2-[(phenylhydroxyphosphinyl)amino]pentanedioic acid;

-[[((hydroxy)phenylmethyl)hydroxyphosphinyl]amino] pentanedioic acid;

-[(butylhydroxyphosphinyl)amino]pentanedioic acid;

2-[[(3-methylbenzyl)hydroxyphosphinyl]amino]pentanedioic acid;

2-[(3-phenylpropylhydroxyphosphinyl)amino]pentanedioic acid;

2-[[(4-fluorophenyl)hydroxyphosphinyl]amino]pentanedioic acid;

2-[(methylhydroxyphosphinyl)amino]pentanedioic acid;

2- [ (phenylethylhydroxyphosphinyl)amino]pentanedioic acid;

-[[(4-methylbenzyl)hydroxyphosphinyl]amino]pentanedioic acid;

2-[[(4-fluorobenzyl)hydroxyphosphinyl]amino]pentanedioic acid;

2- [ [(4-methoxybenzyl)hydroxyphosphinyl]amino]pentanedioic acid;

2-[[(2-fluorobenzyl)hydroxyphosphinyl]amino]pentanedioic acid;

-[[(pentafluorobenzyl)hydroxyphosphinyl]amino] pentanedioic acid;

2-[(phosphono)amino]pentanedioic acid;

2-[[(3-trifluoromethylbenzyl)hydroxyphosphinyl]amino] pentanedioic acid; and a pharmaceutically acceptable salt, hydrate, or a mixture thereof.

63. The use of claim 53, vvherein R_x or R₂ is heterocyclic and X is CH₂.

64. The use of claim 63, vvherein the NAALADase inhibitor is selected from the group consisting of:

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- [[(4-thienyl)hydroxyphosphinyl]methyl]pentanedioic acid;

3- [(2-pyridyl)hydroxyphosphinyl]-2-phenylpropanoic acid;

3-[(3-pyridyl)hydroxyphosphinyl]-2-phenylpropanoic acid;

3-[(4-pyridyl)hydroxyphosphinyl]-2-phenylpropanoic acid;

3-[(tetrahydrofuranyl)hydroxyphosphinyl]-2-phenylpropanoic acid;

3-[(2-indolyl)hydroxyphosphinyl]-2-phenylpropanoic acid;

3-[(3-indolyl)hydroxyphosphinyl]-2-phenylpropanoic acid;

3-[(4-indolyl)hydroxyphosphinyl]-2-phenylpropanoic acid;

3-[(2-thienyl)hydroxyphosphinyl]-2-phenylpropanoic acid;

3-[(3-thienyl)hydroxyphosphinyl]-2-phenylpropanoic acid;

3-[(4-thienyl)hydroxyphosphinyl]-2-phenylpropanoic acid;

3-(benzylhydroxyphosphinyl)-2-(2-pyridyl)propanoic acid;

3-(benzylhydroxyphosphinyl)-2-(3-pyridyl)propanoic acid;

3-(benzylhydroxyphosphinyl)-2-(4-pyridyl)propanoic acid;

3-(benzylhydroxyphosphinyl)-2-(tetrahydrofuranyl)propanoic acid;

3-(benzylhydroxyphosphinyl)-2-(2-indolyl)propanoic acid;

3-(benzylhydroxyphosphinyl)-2-(3-indolyl)propanoic acid;

3-(benzylhydroxyphosphinyl)-2-(4-indolyl)propanoic acid;

3-(benzylhydroxyphosphinyl)-2-(2-thienyl)propanoic acid;

3-(benzylhydroxyphosphinyl)-2-(3-thienyl)propanoic acid;

65. The use of ciaim 63, vvherein or R₂ is heterocyclic and X is oxygen.

66. The use of ciaim 65, vvherein the NAAIADase inhibitor is selected from the group consisting of:

2-[[(2-pyridyl)hydroxyphosphinyl]oxy]pentanedioic acid;

2-[[(3-pyridyl)hydroxyphosphinyl]oxy]pentanedioic acid;

2-[[(4-pyridyl)hydroxyphosphinyl]oxy]pentanedioic acid;

2-[[(tetrahydrofuranyl)hydroxyphosphinyl]oxy]pentanedioic acid ;

2-[[(2-indolyl)hydroxyphosphinyl]oxy]pentanedioic acid;

2-[[(3-indolyl)hydroxyphosphinyl]oxy]pentanedioic acid;

2-[[(4-indolyl)hydroxyphosphinyl]oxy]pentanedioic acid;

2-[[(2-thienyl)hydroxyphosphinyl]oxy]pentanedioic acid;

-[[(3-thienyl)hydroxyphosphinyl]oxy]pentanedioic acid;

2-[[(4-thienyl)hydroxyphosphinyl]oxy]pentanedioic acid;

2-[[(2-pyridyl)hydroxyphosphinyl]oxy]-2-phenylethanoic acid;

2-[[(3-pyridyl)hydroxyphosphinyl]oxy]-2-phenylethanoic acid;

2-[[(4-pyridyl)hydroxyphosphinyl]oxy]-2-phenylethanoic acid;

2-[[(tetrahydrofuranyl)hydroxyphosphinyl]oxy]-2-phenyl ethanoic acid;

2- [ [(2-indolyl)hydroxyphosphinyl]oxy]-2-phenylethanoic acid;

2-[[(3-indolyl)hydroxyphosphinyl]oxy]-2-phenylethanoic acid;

2-[[(4-indolyl)hydroxyphosphinyl]oxy]-2-phenylethanoic acid;

- [ [ (2-thienyl)hydroxyphosphinyl]oxy]-2-phenylethanoic acid;

2- [ [ (3-thienyl)hydroxyphosphinyl]oxy]-2-phenylethanoic acid;

2-[[(4-thienyl)hydroxyphosphinyl]oxy]-2-phenylethanoic acid;

2-[[benzylhydroxyphosphinyl]oxy]-2-(2-pyridyl)ethanoic acid;

2-[[benzylhydroxyphosphinyl]oxy]-2-(3-pyridyl)ethanoic acid;

2-[[benzylhydroxyphosphinyl]oxy]-2-(4-pyridyl)ethanoic acid;

2-[[benzylhydroxyphosphinyl]oxy]-2-(tetrahydrofuranyl) ethanoic acid;

2-[[benzylhydroxyphosphinyl]oxy]-2-(2-indolyl)ethanoic acid;

2-[[benzylhydroxyphosphinyl]oxy]-2-(3-indolyl)ethanoic acid;

2-[[benzylhydroxyphosphinyl]oxy]-2-(4-indolyl)ethanoic acid;

-[[benzylhydroxyphosphinyl]oxy]- 2 -(2 -thienyl)ethanoic acid;

2-[[benzylhydroxyphosphinyl]oxy]-2-(3-thienyl)ethanoic acid;

100

2-[[benzylhydroxyphosphinyl]oxy]-2-(4-thienyl)ethanoic acid and a pharmaceutically acceptable salt, hydrate, or a mixture thereof.

67. The use of claim 53, vvherein or R₂ is heterocyclic and X is NR .

68. The use of claim 67, vvherein the NAALADase inhibitor is a compound selected from the group consisting of:

2-[[(2-pyridyl)hydroxyphosphinyl]amino]pentanedioic acid; 2 -[[(3-pyridyl)hydroxyphosphinyl]amino]pentanedioic acid; 2-[[(4-pyridyl)hydroxyphosphinyl]amino] pentanedioic acid; 2-[[(tetrahydrofuranyl)hydroxyphosphinyl]amino] pentanedioic acid;

2-[[(2-indolyl)hydroxyphosphinyl]amino]pentanedioic acid; 2-[[(3-indolyl)hydroxyphosphinyl]amino]pentanedioic acid; 2 - [ [(4-indolyl)hydroxyphosphinyl]amino]pentanedioic acid; 2-[[(2-thienyl)hydroxyphosphinyl]amino]pentanedioic acid; 2-[[(3-thienyl)hydroxyphosphinyl]amino]pentanedioic acid; 2-[[(4-thienyl)hydroxyphosphinyl]amino]pentanedioic acid; 2-[[(2-pyridyl)hydroxyphosphinyl]amino]-2-phenylethanoic acid;

2-[[(3-pyridyl)hydroxyphosphinyl]amino]-2-phenylethanoic acid;

2-[[(4-pyridyl)hydroxyphosphinyl]amino]-2-phenylethanoic acid;

2-[[(tetrahydrofuranyl)hydroxyphosphinyl]amino]-2-phenyl ethanoic acid;

2-[[(2-indolyl)hydroxyphosphinyl]amino] -2-phenylethanoic acid;

2-[[(3-indolyl)hydroxyphosphinyl]amino]-2-phenylethanoic acid;

2-[[(4-indolyl)hydroxyphosphinyl]amino]-2-phenylethanoic

101 acid;

2-[[(2-thienyl)hydroxyphosphinyl]amino] -2-phenylethanoic acid;

2-[[(3-thienyl)hydroxyphosphinyl]amino]-2-phenylethanoic acid;

2-[[(4-thienyl)hydroxyphosphinyl]amino]-2-phenylethanoic acid;

2-[[benzylhydroxyphosphinyl]amino]-2-(2-pyridyl)ethanoic acid;

2-[[benzylhydroxyphosphinyl]amino]-2-(3-pyridyl)ethanoic acid;

2-[[benzylhydroxyphosphinyl]amino]-2-(4-pyridyl)ethanoic acid;

2-[[benzylhydroxyphosphinyl]amino]-2-(tetrahydrofuranyl) ethanoic acid;

2-[[benzylhydroxyphosphinyl]amino]-2-(2-indolyl)ethanoic acid;

2-[[benzylhydroxyphosphinyl]amino]-2-(3-indolyl)ethanoic acid;

2-[[benzylhydroxyphosphinyl]amino]-2-<4-indolyl)ethanoic acid;

2-[[benzylhydroxyphosphinyl]amino]-2-(2-thienyl)ethanoic acid;

2-[[benzylhydroxyphosphinyl]amino]-2-(3-thienyl)ethanoic acid;

2-[[benzylhydroxyphosphinyl]amino]-2-(4-thienyl)ethanoic acid and a pharmaceutically acceptable salt, hydrate, or a mixture thereof.

Claims

1. NAALADāzes inhibitora pielietojums vēža ārstēšanai dzīvniekiem, kuri cieš no vēža.

2. Pielietojums saskaņā ar 1. punktu, kas atšķiras ar to, ka NAALADāzes inhibitoru izvēlas no grupas, kas sastāv no: glutamāta atvasinājuma oksifosfinilatvasinājuma; skābā peptīda analoga; konformācijas ziņā traucētas glutamāta imitētājvielas; un šo vielu maisījumiem.

3. Pielietojums saskaņā ar 2. punktu, kas atšķiras ar to, ka NAALADāzes inhibitors ir glutamāta atvasinājuma oksifosfinilatvasinājums.

4. Pielietojums saskaņā ar 1. punktu, kas atšķiras ar to, ka NAALADāzes inhibitoru lieto kopā ar papildu terapeitisku līdzekli, kuru izvēlas no grupas, kas sastāv no: terapeitiskiem hormoniem, ķimioterapeitiskiem hormoniem, anti-angioģenēzes līdzekļiem, ar radioaktīvo izotopu iezīmētiem savienojumiem un šo vielu maisījumiem.

5. Pielietojums saskaņā ar 1. punktu, kas atšķiras ar to, ka vēzis ir audzējs no grupas: ACTH producējošs audzējs, akūta limfocitārā leikēmija, akūta nelimfocitārā leikēmija, virsnieru dziedzera garozas vēzis, urīnpūšļa vēzis, galvas smadzeņu vēzis, krūts dziedzera vēzis, cervikāla vēzis, hroniska limfoleikēmija, hroniska mieloleikēmija, taisnās zarnas vēzis, ādas T-šūnu limfoma, endometrija vēzis, barības vada vēzis, Jūinga sarkoma, ultspūšļa vēzis, mataino šūnu leikēmija, galvas un kakla vēzis, Hodžkina limfoma, Kapoši sarkoma, nieru vēzis, aknu vēzis, plaušu vēzis, plaušu vēzis (smalkšūnu un/vai lielšūnu), ļaundabīgā peritoneālā efūzija, ļaundabīgā pleirālā efūzija, melanoma, mezotelioma, multiplā mieloma, neirobiastoma, ne-Hodžkina limfoma, osteosarkoma, olnīcu vēzis, olnīcu (dzimumšūnu) vēzis, aizkuņģa dziedzera vēzis, dzimumlocekļa vēzis, prostatas vēzis, retinoblastoma, ādas vēzis, mīksto audu vēzis, zvīņveida šūnu karcinomas, kuņģa vēzis, sēklinieka vēzis, vairogdziedzera vēzis, trofoblasta neoplazmas, dzemdes vēzis, maksts vēzis, vulvas vēzis un Vilmsa audzējs.

6. Pielietojums saskaņā ar 1. punktu, kas atšķiras ar to, ka vēža slimība ir prostatas adenokarcinoma.

7. Pielietojums saskaņā ar 1. punktu, kas atšķiras ar to, ka vēža slimību izvēlas no grupas, kas sastāv no: galvas smadzeņu vēža, virsnieru dziedzera garozas vēža, nieru vēža un sēklinieka vēža.

8. Pielietojums saskaņā ar 1. punktu, kas atšķiras ar to, ka NAALADāzes inhibitorā ietilpst savienojums ar sekojošu formulu:

O

Rl -p·

OH

R2

X^ COOH

Formula I, kur

R, ir ūdeņraža atoms, C, - C₉ alkilgrupa ar taisnu vai sazarotu virkni, C₂ - C₉ alkenilgrupa ar taisnu vai sazarotu virkni, C₃ - C₈ cikloaikil-, C₅ - C₇ cikloalkenil- vai Ar,- grupa;

X ir CH₂-grupa, skābekļa atoms vai NR,-grupa, kur R, ir definēts iepriekš; un

R₂ ir C, - C₉ alkilgrupa ar taisnu vai sazarotu virkni, C₂ - C₉alkenilgrupa ar taisnu vai sazarotu virkni, C₃ - C₈cikloaikil-, C₅ - C₇ cikloalkenil- vai Ar,- grupa; šī alkil-, alkenil-, cikloaikil-, cikloalkenil- vai arilgrupa var būt aizvietota ar karbonskābi;

minētās alkil-, alkenil-, cikloaikil-, cikloalkenil- vai arilgrupas var būt aizvietotas ar C₃ - C₈ cikloaikil-, C₃ - vai C₅ cikloaikil-, C₅ - C₇ cikloalkenil-, C, - C₄ alkil-, C, - C₄ alkenilgrupām, halogēna atomu, oksi-, karboksi- nitro,trifluormetilgrupām, C, - C₆ alkil- vai C, - C₆ alkenilgrupu ar taisnu vai sazarotu virkni, C, - C₄ alkoksi-, C, - C₄ alkeniloksi-, fenoksi-, benziloksi-, amino- vai Ar,-grupu un kur Ar,-grupu izvēlas no grupas, kura sastāv no

1-naftil-, 2-naftil-, 2-indolil-, 3-indolil-, 4-indolil-, 2-furil-, 3-furil-, tetrahidrofuranil-, 2-tienil-, 3-tienil-, 4-tienil-, 2-, 3-, vai 4-piridil- vai fenilgrupas, kas satur no viena līdz pieciem aizvietotājiem, kurus neatkarīgi izvēlas no grupas, kas sastāv no ūdeņraža atoma, halogēna atoma, oksi-, karboksi-, nitro-, trifluormetil-, C, - C₆ alkil- vai - C₆ alkenilgrupas ar taisnu vai sazarotu virkni, - C₄ alkoksi- vai - C₄ alkeniloksi-, fenoksi-, benziloksi- un aminogrupām; vai šī savienojuma farmaceitiski pieņemami sāļi, hidrāti vai vielu maisījumi.

9. Pielietojums saskaņā ar 8. punktu, kas atšķiras ar to, ka R, un R₂ ir alifātiskas grupas ar taisnu vai sazarotu virkni vai karbocikliskas grupas un X ir CH₂-grupa.

10. Pielietojums saskaņā ar 9. punktu, kas atšķiras ar to, ka NAALADāzes inhibitoru izvēlas no grupas, kas sastāv no:

2-[[metiloksifosfinil]metil]glutārskābes;

2-[[etiloksifosfinil]metil]glutārskābes;

2-[[propiloksifosfinil]metil]glutārskābes;

2-[[butiloksifosfinil]metiI]glutārskābes;

2-[[cikloheksiloksifosfinil]metil]glutārskābes;

2-[[(cikIoheksil)metiloksifosfinil]metil]glutārskābes;

2-[[feniloksifosfinil]metil]glutārskābes;

2-[[benziloksifosfinil]metil]glutārskābes;

2-[[feniletiloksifosfinil]metil]glutārskābes;

2-[[fenilpropiloksifosfinil]metil]glutārskābes;

2-[[fenilbutiloksifosfinil]metil]glutārskābes;

2-[[(4-metilbenzil)oksifosfinil]metil]glutārskābes;

2-[[(4-fluorbenzil)oksifosfinil]metil]glutārskābes;

2-[[(2-fluorbenzil)oksifosfinil]metil]glutārskābes;

2-[[(pentafluorbenzil)oksifosfinil]metil]glutārskābes;

2-[[(metoksibenzil)oksifosfinil]metil]glutārskābes;

2-[[(2,3,4-trimetoksifenil)oksifosfinil]metil]glutārskābes;

2-[[(1 -naftil)oksifosfiniljmetil]glutārskābes;

2-[[(2-naftii)oksifosfīnil]metiI]glutārskābes;

2-[[(1-naftil)metiloksifosfinil]metil]glutārskābes;

2-[[(2-naftil)metiloksifosfinil]metil]glutārskābes;

2-[[(1-naftil)etiloksifosfinil]metil]glutārskābes;

2-[[(2-naftil)etiloksifosfinil]metil]glutārskābes;

2-[[(1-naftil)propiloksifosfinil]metil]glutārskābes;

2-[[(2-naftil)propiloksifosfinil]metil]glutārskābes;

2-[[(1 -naftil)butiloksifosfinil]metil]glutārskābes;

2-[[(2-naftil)butiloksifosfinil]metil]glutārskābes;

2-[[(fenilprop-2-enil)oksifosfinil]metil]glutārskābes;

2-[[(2-fluorbenzil)oksifosfinil]metil]glutārskābes;

2-[[((oksi)fenilmetil)oksifosfinil]metil]glutārskābes;

2-[[(3-metilbenzil)oksifosfinil]metil]glutārskābes;

2-[[(4-fluorfenil)oksifosfinil]metil]glutārskābes;

2-(fosfonometil)glutārskābes;

2- [[(3-trifluormetilbenzil)oksifosfinil]metil]glutārskābes;

3- (metiloksifosfinil)-2-fenilpropionskābes;

3-(etiloksifosfinil)-2-fenilpropionskābes;

3-(propiloksifosfinil)-2-fenilpropionskābes;

3-(butiloksifosfinil)-2-fenilpropionskābes;

3-(cikloheksiloksifosfinil)-2-fenilpropionskābes;

3-((cikloheksil)metiloksifosfinil)-2-fenilpropionskābes;

3-(feniloksifosfinil)-2-fenilpropionskābes;

3-(benziloksifosfinil)-2-fenilpropionskābes;

3-(feniletiloksifosfinil)-2-fenilpropionskābes;

3-(fenilpropiloksifosfinil)-2-fenilpropionskābes;

3-(fenilbutiloksifosfinil)-2-fenilpropionskābes;

3-((2,3,4-trimetoksifenil)-3-oksifosfinil)-2-fenilpropionskābes;

3-((1-naftil)oksifosfinil)-2-fenilpropionskābes;

3-((2-naftil)oksifosfinil)-2-fenilpropionskābes;

3-((1-naftil)metiloksifosfinil)-2-fenilpropionskābes;

3-((2-naftil)metiloksifosfinil)-2-fenilpropionskābes;

3-((1-naftil)etiloksifosfinil)-2-fenilpropionskābes;

3-((2-naftil)etiloksifosfinil)-2-fenilpropionskābes;

3-((1 -naftil)propiloksifosfinil)-2-fenilpropionskābes;

3-((2-naftil)propiloksifosfinil)-2-fenilpropionskābes;

3-((1 -naftil)butiloksifosfinil)-2-fenilpropionskābes;

3-((2-naftil)butiloksifosfinil)-2-feniIpropionskābes;

5 3-(fenilprop-2-eniloksifosfinil)-2-fenilpropionskābes;

2-[(benziloksifosfinil)rnetil]glutārskābes;

2-[(metiloksifosfinil)metil]adipīnskābes;

2-[(benziloksifosfinil)metil]adipīnskābes;

2-[(metiloksifosfinil)metil]pimelīnskābes;

10 2-[(benziloksifosfinil)metil]pimelīnskābes;

2-[(metiloksifosfinil)metil]heksāndikarbonskābes;

2-[(benziloksifosfinil)metil]heksāndikarbonskābes;

2-[(metiloksifosfinil)metil]azelaīnskābes;

2-[(benziloksifosfinil)metil]azelaīnskābes;

15 2-[(metiloksifosfinil)metil]sebacīnskābes;

2- [(benziloksifosfinil)metil]sebacīnskābes;

3- (benziloksifosfinil)-2-metilpropionskābes;

3-(benziloksifosfinil)-2-etilpropionskābes;

3-(benziloksifosfinil)-2-propilpropionskābes;

20 3-(benziloksifosfinil)-2-butilpropionskābes;

3-(benziloksifosfinil)-2-cikloheksilpropionskābes;

3-(benziloksifosfinil)-2-(cikloheksil)metilpropionskābes;

3-(benziloksifosfinil)-2-fenilpropionskābes;

3-(benziloksifosfinil)-2-benzilpropionskābes;

25 3-(benziloksifosfinil)-2-feniletilpropionskābes;

3-(benziloksifosfinil)-2-fenilpropilpropionskābes;

3-(benziloksifosfinil)-2-fenilbutilpropionskābes;

3-(benziloksifosfinil)-2-(2,3,4-trimetoksifenil)propionskābes;

3-(benziloksifosfinil)-2-(1-naftil)propionskābes;

30 3-(benziloksifosfinil)-2-(2-naftil)propionskābes;

3-(benziloksifosfinil)-2-(1-naftil)metilpropionskābes;

3-(benziloksifosfinil)-2-(2-naftil)metilpropionskābes;

3-(benziloksifosfinil)-2-(1 -naftil)etilpropionskābes;

3-(benziloksifosfinil)-2-(2-naftil)etilpropionskābes;

3-(benziloksifosfinil)-2-(1-naftil)propilpropionskābes;

3-(benziloksifosfinil)-2-(2-naftil)propilpropionskābes;

5 3-(benzi loksif osf in il)-2-( 1 -naftil)butilpropionskābes;

3-(benziloksifosfinil)-2-(2-naftil)butilpropionskābes;

3-(benziloksifosfinil)-2-fenilprop-2-enilpropionskābes;

2-[[(2-piridil)metiloksifosfinil]metil]glutārskābes;

2-[[(3-piridil)metiloksifosfinil]metil]glutārskābes;

10 2-[[(4-piridil)metiloksifosfinil]metil]glutārskābes;

2-[[(3-piridil)etiloksifosfinil]metil]glutārskābes;

2-[[(3-piridil)propiloksifosfinil]metil]glutārskābes;

2-[[(tetrahidrofuranil)metiloksifosfinil]metil]glutārskābes;

2-[[(tetrahidrofuranil)etiloksifosfinil]metil]glutārskābes;

15 2-[[(tetrahidrofuranil)propiloksifosfinil]metil]glutārskābes;

2-[[(2-indolil)metiloksifosfinil]metiljglutārskābes;

2-[[(3-indolil)metiloksifosfinil]metil]glutārskābes;

2-[[(4-indolil)metiloksifosfinil]metil]glutārskābes;

2-[[(3-indolil)etiloksifosfinil]metil]glutārskābes;

20 2-[[(3-indolil)propiloksifosfinil]metii]glutārskābes;

2-[[(2-tienil)metiloksifosfinil]metil]glutārskābes;

2-[[(3-tienil)metiloksifosfinil]metil]glutārskābes;

2-[[(4-tienil)metiloksifosfinil]metil]glutārskābes;

2- [[(3-tienil)etiloksifosfinil]metil]glutārskābes;

25 2-[[(3-tienil)propiloksifosfinil]metil]glutārskābes;

3- [(2-piridil)metiloksifosfinil]-2-fenilpropionskābes;

3-[(3-piridil)metiloksifosfinil]-2-fenilpropionskābes;

3-[(4-piridil)metiloksifosfinil]-2-fenilpropionskābes;

3-[(3-piridii)etiloksifosfinil]-2-fenilpropionskābes;

30 3-[(3-piridil)propiloksifosfinil]-2-fenilpropionskābes;

3-[(tetrahidrofuranil)metiloksifosfinil]-2-fenilpropionskābes;

3-[(tetrahidrofuranil)etiloksifosfinil]-2-fenilpropionskābes;

Ί

3-[(tetrahidrofuranil)propiloksifosfinil]-2-fenilpropionskābes;

3-[(2-indolil)metiloksifosfinil]-2-fenilpropionskābes;

3-[(3-indolil)metiloksifosfinil]-2-fenilpropionskābes;

3-[(4-indolil)metiloksifosfinil]-2-fenilpropionskābes;

5 3-[(3-indolil)etiloksifosfiniI]-2-fenilpropionskābes;

3-[(3-indolil)propiloksifosfinil]-2-fenilpropionskābes;

3-[(2-tienil)metiloksifosfinil]-2-fenilpropionskābes;

3-[(3-tienil)metiloksifosfinil]-2-fenilpropionskābes;

3-[(4-tienil)metiloksifosfinil]-2-fenilpropionskābes;

10 3-[(3-tienil)etiloksifosfinil]-2-fenilpropionskābes;

3-[(3-tienil)propiloksifosfinil]-2-fenilpropionskābes;

3-(benziloksifosfinil)-2-(2-piridil)metilpropionskābes; 3-(benziloksifosfinil)-2-(3-piridil)metilpropionskābes; 3-(benziloksifosfinil)-2-(4-piridil)metilpropionskābes;

15 3-(benziloksifosfinil)-2-(3-piridil)etilpropionskābes;

3-(benziloksifosf inil)-2-(3-piridil)propilpropionskābes; 3-(benziloksifosfinil)-2-(tetrahidrofuranil)metilpropionskābes; 3-(benziloksifosfinil)-2-(tetrahidrofuranil)etilpropionskābes; 3-(benziloksifosfinil)-2-(tetrahidrofuranil)propilpropionskābes;

20 3-(benziloksifosfinil)-2-(2-indolil)metilpropionskābes; 3-(benziloksifosfinil)-2-(3-indolil)metilpropionskābes; 3-(benziloksifosfinil)-2-(4-indolil)metilpropionskābes; 3-(benziloksifosfinil)-2-(3-indolil)etilpropionskābes; 3-(benziloksifosfinil)-2-(3-indolil)propilpropionskābes;

25 3-(benziloksifosfinil)-2-(2-tienil)metilpropionskābes; 3-(benziloksifosfinil)-2-(3-tienil)metilpropionskābes; 3-(benziloksifosfinil)-2-(4-tienii)metilpropionskābes; 3-(benziloksifosfinil)-2-(3-tienil)etilpropionskābes; 3-(benziloksifosfinil)-2-(3-tienil)propilpropionskābes;

30 un farmaceitiski pieņemama sāls, hidrāta vai vielu maisījuma.

11. Pielietojums saskaņā ar 9. punktu, kas atšķiras ar to, ka NAALADāzes inhibitoru izvēlas no grupas, kas sastāv no:

2-[(benziloksifosfinil)metil]glutārskābes;

2-[(feniloksifosfinil)metil]glutārskābes;

2-[[((oksi)fenilmetil)oksifosfinil]metil]glutārskābes;

2-[(butiloksifosfinil)metil]glutārskābes;

2-[[(3-metilbenzil)oksifosfinil]metil]glutārskābes;

2-[(3-fenilpropiloksifosfinil)metil]glutārskābes;

2-[[(4-fluorfenil)oksifosfinil]metil]glutārskābes;

2-[(metiloksifosfinil)metil]glutārskābes;

2-[(feniletiloksifosfinil)metil]glutārskābes;

2-[[(4-metilbenzil)oksifosfinil]metii]glutārskābes;

2-[[(4-fluorbenzil)oksifosfinil]metil]glutārskābes;

2-[[(4-metoksibenzil)oksifosfinil]metil]glutārskābes;

2-(fosfonometil)glutārskābes;

2-[[(3-trifluormetilbenzil)oksifosfinil]metil]gliitārskābes;

2-[[(2-fluorbenzil)oksifosfinil]metil]glutārskābes;

2-[[(pentafluorbenzil)oksifosfinil]metil]glutārskābes;

un farmaceitiski pieņemama sāls, hidrāta vai vielu maisījuma.

12. Pielietojums saskaņā ar 8. punktu, kas atšķiras ar to, ka R, un R₂ ir alifātiskas grupas ar taisnu vai sazarotu virkni vai karbocikliskas grupas un X ir skābekļa atoms.

13. Pielietojums saskaņā ar 12. punktu, kas atšķiras ar to, ka NAALADāzes inhibitoru izvēlas no grupas, kas sastāv no: 2-[[metiloksifosfinil]oksi]glutārskābes;

2-[[etiloksifosfinil]oksi]glutārskābes;

2-[[propiloksifosfinil]oksi]glutārskābes;

2-[[butiloksifosfinil]oksi]glutārskābes;

2-[[cikloheksiloksifosfinil]oksi]glutārskābes;

2-[[(cikloheksil)metiloksifosfinil]oksi]glutārskābes;

2-[[feniloksifosfinil]oksi]glutārskābes;

2-[[benziloksifosfinil]oksi]glutārskābes;

2-[[feniletiloksifosfiniI]oksi]glutārskābes;

2-[[fenilpropiloksifosfinil]oksi]glutārskābes;

2-[[fenilbutiloksifosfinil]oksi]glutārskābes;

2-[[(4-metilbenzil)oksifosfinil]oksi]glutārskābes;

2-[[(4-fluorbenzil)oksifosfinil]oksi]glutārskābes;

2-[[(2-fluorbenzil)oksifosfinil]oksi]glutārskābes;

2-[[(pentafluorbenzil)oksifosfinil]oksi]glutārskābes;

2-[[(metoksibenzil)oksifosfinil]oksi]glutārskābes;

2-[[(2,3,4-trimetoksifenil)oksifosfinil]oksi]glutārskābes;

2-[[(1-naftil)oksifosfinil]oksi]glutārskābes;

2-[[(2-naftil)oksifosfinil]oksi]glutārskābes;

2-[[(1 -naftil)metiloksifosfinil]oksi]glutārskābes; 2-[[(2-naftil)metiloksifosfinil]oksi]glutārskābes;

2-[[(1 -naftil)etiloksifosfinil]oksi]glutārskābes;

2-[[(2-naftil)etiloksifosfinil]oksi]glutārskābes;

2-[[(1-naftil)propiloksifosfinil]oksi]glutārskābes;

2-[[(2-naftil)propiloksifosfinil]oksi]glutārskābes;

2-[[(1-naftil)butiloksifosfinil]oksi]glutārskābes;

2-[[(2-naftil)butiloksifosfinil]oksi]glutārskābes;

2-[[(fenilprop-2-enil)oksifosfinil]oksi]glutārskābes;

2-[[benziloksifosfinil]oksi]glutārskābes;

2-[[((oksi)fenilmetil)oksifosfinil]oksi]glutārskābes;

2-[[(3-metilbenzil)oksifosfinil]oksi]glutārskābes;

2-[[(4-fluorfenil)oksifosfinil]oksi]glutārskābes;

2-[[(2-fluorbenzil)oksifosfinil]oksi]glutārskābes;

2-[(fosfono)oksi]glutārskābes;

2-[[(3-trifluormetilbenzil)oksifosfinil]oksi]glutārskābes;

2-[[metiloksifosfinil]oksi]-2-feniletiķskābes;

2-[[etiloksifosfinil]oksi]-2-feniletiķskābes;

2-[[propiloksifosfinil]oksi]-2-feniletiķskābes;

2-[[butiloksifosfinil]oksi]-2-feniletiķskābes;

2-[[cikloheksiloksifosfinil]oksi]-2-feniletiķskābes;

2-[[(cikloheksil)metiloksifosfinil]oksi]-2-feniletiķskābes;

2-[[feniloksifosfinil]oksi]-2-feniletiķskābes;

2-[[benziloksifosfinil]oksi]-2-feniletiķskābes;

2-[[feniletiloksifosfinil]oksi]-2-feniletiķskābes;

2-[[fenilpropiloksifosfinil]oksi]-2-feniletiķskābes;

2-[[fenilbutiloksifosfinil]oksi]-2-feniletiķskābes;

2-[[(2,3,4-trimetoksifenil)-3-oksifosfinil]oksi]-2-feniletiķskābes; 2-[[(1 -naftil)oksifosfinil]oksi]-2-feniletiķskābes; 2-[[(2-naftil)oksifosfinil]oksi]-2-feniletiķskābes;

2-[[(1 -naftil)metiloksifosfinil]oksi]-2-feniletiķskābes; 2-[[(2-naftil)metiloksifosfinil]oksi]-2-feniletiķskābes;

2-[[(1 -naftil)etiloksifosfinil]oksi]-2-feniletiķskābes; 2-[[(2-naftil)etiloksifosfinil]oksi]-2-feniletiķskābes;

2-[[(1 -naftil)propiloksifosfinil]oksi]-2-feniletiķskābes;

2-[[(2-naftil)propiloksifosfiniI]oksi]-2-feniletiķskābes;

2-[[(1-naftil)butiloksifosfinil]oksi]-2-feniletiķskābes;

2-[[(2-naftil)butiloksifosfinil]oksi]-2-feniletiķskābes;

2-[[fenilprop-2-eniloksifosfinil]oksi]-2-feniletiķskābes;

2-[(metiloksifosfinil)oksi]adipīnskābes;

2-[(benziloksifosfinil)oksi]adipīnskābes;

2-[(metiloksifosfinil)oksi]pimelīnskābes;

2-[(benziloksifosfinil)oksi]pimelīnskābes;

2-[(metiloksifosfinil)oksi]heksāndikarbonskābes;

2-[(benziloksifosfinil)oksi]heksāndikarbonskābes;

2-[(metiloksifosfinil)oksi]azelaīnskābes;

2-[(benziloksifosfinil)oksi]azelaīnskābes;

2-[(metiloksifosfinil)oksi]sebacīnskābes;

2-[(benziloksifosfinil)oksi]sebacīnskābes;

2-[[benziloksifosfinil]oksi]-2-metiletiķskābes;

2-[[benziloksifosfinil]oksi]-2-etiletiķskābes;

2-[[benziloksifosfinil]oksi]-2-propiletiķskābes;

2-[[benziloksifosfinil]oksi]-2-butiletiķskābes;

2-[[benziloksifosfinil]oksi]-2-cikloheksiletiķskābes;

2-[[benziloksifosfinil]oksi]-2-(cikloheksil)metiletiķskābes;

2-[[benziloksifosfinil]oksi]-2-feniletiķskābes;

2-[[benziloksifosfinil]oksi]-2-benziletiķskābes;

2-[[benziloksifosfinil]oksi]-2-feniletiletiķskābes;

2-[[benziloksifosfinil]oksi]-2-fenilpropiletiķskābes;

5 2-[[benziloksifosfinil]oksi]-2-fenilbutiletiķskābes;

2-[[benziloksifosfinil]oksi]-2-(2,3,4-trimetoksifenil)etiķskābes; 2-[[benziIoksifosfinil]oksi]-2-(1 -naftil)etiķskābes; 2-[[benziloksifosfinil]oksi]-2-(2-naftil)etiķskābes; 2-[[benziloksifosfinil]oksi]-2-(1 -naftil)metiletiķskābes;

10 2-[[benziloksif osf in i l]oksi]-2-(2-nafti I) metileti ķskābes;

2-[[benziloksifosfinil]oksi]-2-(1-naftil)etiletiķskābes; 2-[[benziloksifosfinil]oksi]-2-(2-naftil)etiletiķskābes; 2-[[benziloksifosfinil]oksi]-2-(1 -naftil)propiletiķskābes; 2-[[benziloksifosfinil]oksi]-2-(2-naftil)propiletiķskābes;

15 2-[[benziloksif osf in ilļoks i]-2-(1 -nafti I) buti Iet iķskābes;

2-[[benziloksifosfinil]oksi]-2-(2-naftil)butiletiķskābes; 2-[[benziloksifosfinil]oksi]-2-fenilprop-2-eniletiķskābes; 2-[[(2-piridil)metiloksifosfinil]oksi]giutārskābes; 2-[[(3-piridil)metiloksifosfinil]oksi]glutārskābes;

20 2-[[(4-piridil)metiloksifosfinil]oksi]glutārskābes; 2-[[(3-piridil)etiloksifosfinil]oksi]glutārskābes; 2-[[(3-piridil)propiloksifosfinil]oksi]glutārskābes; 2-[[(tetrahidrofuranil)metiloksifosfinil]oksi]glutārskābes; 2-[[(tetrahidrofuranil)etiloksifosfinil]oksi]glutārskābes;

25 2-[[(tetrahidrofuranil)propiioksifosfinil]oksi]glutārskābes; 2-[[(2-indolil)metiloksifosfinil]oksi]glutārskābes; 2-[[(3-indolil)metiioksifosfinil]oksi]glutārskābes; 2-[[(4-indolil)metiloksifosfinil]oksi]glutārskābes; 2-[[(3-indolil)etiloksifosfinil]oksi]glutārskābes;

30 2-[[(3-indolil)propiloksifosfinil]oksi]glutārskābes; 2-[[(2-tienil)metiloksifosfinil]oksi]glutārskābes; 2-[[(3-tienil)metiloksifosfinil]oksi]glutārskābes;

2-[[(4-tienil)metiloksifosfinil]oksi]glutārskābes;

2-[[(3-tienil)etiloksifosfinil]oksi]glutārskābes;

2-[[(3-tienil)propiloksifosfinil]oksi]glutārskābes;

2-[[(2-piridil)metiloksifosfinil]oksi]-2-feniletiķskābes;

2-[[(3-piridil)metiloksifosfinil]oksi]-2-feniletiķskābes;

2-[[(4-piridil)metiloksifosfinil]oksi]-2-feniletiķskābes;

2-[[(3-piridil)etiloksifosfinil]oksi]-2-feniletiķskābes;

2-[[(3-piridil)propiloksifosfinil]oksi]-2-feniletiķskābes;

2-[[(tetrahidrofuranil)metiloksifosfinil]oksi]-2-feniletiķskābes;

2-[[(tetrahidrofuranil)etiloksifosfinil]oksi]-2-feniletiķskābes;

2-[[(tetrahidrofuranil)propiloksifosfinil]oksi]-2-feniletiķskābes;

2-[[(2-indolil)metiloksifosfinil]oksi]-2-feniletiķskābes;

2-[[(3-indolil)metiloksifosfinil]oksi]-2-feniletiķskābes;

2-[[(4-indolil)metiloksifosfinil]oksi]-2-feniletiķskābes;

2-[[(3-indolil)etiloksifosfinil]oksi]-2-feniletiķskābes;

2-[[(3-indolil)propiloksifosfinil]oksi]-2-feniletiķskābes;

2-[[(2-tienil)metiloksifosfinil]oksi]-2-feniletiķskābes;

2-[[(3-tienil)metiloksifosfinil]oksi]-2-feniletiķskābes;

2-[[(4-tienil)metiloksifosfinil]oksij-2-feniletiķskābes;

2-[[(3-tienil)etiloksifosfinil]oksi]-2-feniletiķskābes;

2-[[(3-tienil)propiloksifosfinil]oksi]-2-feniletiķskābes;

2-[[benziloksifosfinil]oksi]-2-(2-piridil)metiletiķskābes;

2-[[benziloksifosfinil]oksi]-2-(3-piridil)metiletiķskābes;

2-[[benziloksifosfinil]oksi]-2-(4-piridil)metiletiķskābes;

2-[[benziloksifosfinil]oksi]-2-(3-piridil)etiletiķskābes;

2-[[benziloksifosfinii]oksi]-2-(3-piridil)propiletiķskābes;

2-[[benziioksifosfinil]oksi]-2-(tetrahidrofuranil)metiletiķskābes;

2-[[benziloksifosfinii]oksi]-2-(tetrahidrofuranil)etiletiķskābes;

2-[[benziloksifosfinil]oksi]-2-(tetrahidrofuranil)propiletiķskābes;

2-[[benziloksifosfinil]oksi]-2-(2-indolil)metiletiķskābes;

2-[[benziloksifosfinil]oksi]-2-(3-indolil)metiletiķskābes;

2-[[benziloksifosfinil]oksi]-2-(4-indolil)metiletiķskābes;

2-[[benziloksifosfinil]oksi]-2-(3-indolii)etiletiķskābes;

2-[[benziloksifosfinil]oksi]-2-(3-indolil)propiletiķskābes;

2-[[benziloksifosfinil]oksi]-2-(2-tienil)metiletiķskābes;

2-[[benziloksifosfinil]oksi]-2-(3-tienil)metiletiķskābes;

2-[[benziloksifosfinil]oksij-2-(4-tienil)metiletiķskābes;

2-[[benziloksifosfinil]oksi]-2-(3-tienil)etiletiķskābes;

2-[[benziloksifosfinil]oksi]-2-(3-tienil)propiletiķskābes;

un farmaceitiski pieņemama sāls, hidrāta un vielu maisījuma.

14. Pielietojums saskaņā ar 12. punktu, kas atšķiras ar to, ka NAALADāzes inhibitoru izvēlas no grupas, kas sastāv no: 2-[(benziloksifosfinil)oksi]glutārskābes;

2-[(feniloksifosfinil)oksi]glutārskābes;

2-[[((oksi)fenilmetil)oksifosfiniljoksi]glutārskābes;

2-[(butiloksifosfinil)oksi]glutārskābes;

2-[[(3-metilbenzil)oksifosfinil]oksi]glutārskābes;

2-[(3-fenilpropiloksifosfinil)oksiļglutārskābes;

2-[[(4-fluorfenil)oksifosfinil]oksi]glutārskābes;

2-[(metiloksifosfinil)oksi]glutārskābes;

2-[(feniletiloksifosfinil)oksi]glutārskābes;

2-[[(4-metilbenzil)oksifosfinil]oksi]glutārskābes;

2-[[(4-fluorbenzil)oksifosfinil]oksiJglutārskābes;

2-[[(4-metoksibenzil)oksifosfinil]oksi]glutārskābes;

2-[(fosfono)oksi]glutārskābes;

2-[[(3-trifluormetilbenzil)oksifosfinil]oksi]glutārskābes:

2-[[(2-fluorbenzil)oksifosfinil]oksi]glutārskābes;

2'[[(pentafluorbenzil)oksifosfiniljoksijglutārskābes;

un farmaceitiski pieņemama sāls, hidrāta vai vielu maisījuma.

15. Pielietojums saskaņā ar 8. punktu, kas atšķiras ar to, ka R, un R₂ ir alifātiskas grupas ar taisnu vai sazarotu virkni vai karbocikliskas grupas un X ir NR,-grupa.

16. Pielietojums saskaņā ar 15. punktu, kas atšķiras ar to, ka NAALADāzes inhibitoru izvēlas no grupas, kas sastāv no:

2-[[metiloksifosfinil]amino]glutārskābes;

2-[[etiloksifosfinil]amino]glutārskābes;

2-[[propiloksifosfinil]amino]glutārskābes;

2-[[butiloksifosfinil]amino]glutārskābes;

2-[[cikloheksiloksifosfinil]amino]glutārskābes;

2-[[(cikloheksil)metiloksifosfinil]amino]glutārskābes;

2-[[feniloksifosfinil]amino]glutārskābes;

2-[[benziloksifosfinil]amino]glutārskābes;

2-[[feniletiloksifosfinil]amino]glutārskābes;

2-[[fenilpropiloksifosfinil]amino]glutārskābes;

2-[[fenilbutiloksifosfinil]amino]glutārskābes;

2-[[(4-metilbenzil)oksifosfinil]amino]glutārskābes;

2-[[(4-fluorbenzil)oksifosfinil]amino]glutārskābes;

2-[[(2-fluorbenzil)oksifosfinil]amino]glutārskābes;

2-[[(pentafluorbenzil)oksifosfinil]amino]glutārskābes;

2-[[(metoksibenzil)oksifosfinil]amino]glutārskābes;

2-[[(2,3,4-trimetoksifenil)oksifosfinil]amino]glutārskābes;

2-[[(1 -naftil)oksifosfinil]amino]glutārskābes;

2-[[(2-naftil)oksifosfinil]amino]glutārskābes;

2-[[(1-naftil)metiloksifosfinil]amino]glutārskābes;

2-[[(2-naftil)metiloksifosfinil]amino]glutārskābes;

2-[[(1-naftil)etiloksifosfinil]amino]glutārskābes;

2-[[(2-naftil)etiloksifosfinil]amino]glutārskābes;

2-[[(1-naftil)propiloksifosfinil]amino]glutārskābes;

2-[[(2-naftil)propiloksifosfinil]amino]glutārskābes;

2-[[(1-naftil)butiloksifosfinil]amino]glutārskābes;

2-[[(2-naftil)butiloksifosfinil]amino]glutārskābes;

2-[[(fenilprop-2-enil)oksifosfinil]amino]glutārskābes;

2-[[benziloksifosfinil]amino]glutārskābes;

2-[[(2-fluorbenzil)oksifosfinil]amino]-2-glutārskābes;

2-[[((oksi)fenilmetil)oksifosfinil]amino]glutārskābes;

2-[[(3-metilbenzil)oksifosfinil]amino]glutārskābes;

2-[[(4-fluorfenil)oksifosfinil]amino]glutārskābes;

2-[(fosfono)amino]glutārskābes;

2-[[(3-trifluormetilbenzil)oksifosfinil]amino]glutārskābes;

2-[[metiloksifosfinil]amino]-2-feniletiķskābes;

5 2-[[etiloksifosfinil]amino]-2-feniletiķskābes; 2-[[propiloksifosfinil]amino]-2-feniletiķskābes; 2-[[butiloksifosfinil]amino]-2-feniletiķskābes; 2-[[cikloheksiloksifosfinil]amino]-2-feniletiķskābes; 2-[[(cikloheksil)metiloksifosfinil]amino]-2-feniletiķskābes;

10 2-[[feniloksifosfinii]amino]-2-feniletiķskābes; 2-[[benziloksifosfinil]amino]-2-feniletiķskābes; 2-[[feniletiloksifosfinil]amino]-2-feniletiķskābes; 2-[[fenilpropiloksifosfinil]amino]-2-feniletiķskābes; 2-[[fenilbutiloksifosfinil]amino]-2-feniletiķskābes;

15 2-[[(2,3,4-trimetoksifenil)-3-oksifosfinil]amino]-2-feniletiķskābes; 2-[[(1-naftil)oksifosfinil]amino]-2-feniletiķskābes; 2-[[(2-naftil)oksifosfinil]amino]-2-feniletiķskābes; 2-[[(1-naftil)metiloksifosfinil]amino]-2-feniletiķskābes; 2-[[(2-naftil)metiloksifosfinil]amino]-2-feniletiķskābes;

20 2-[[( 1 -naftil)etiloksifosfinil]amino]-2-feniletiķskābes;

2-[[(2-naftil)etiloksifosfinil]amino]-2-feniletiķskābes; 2-[[(1-naftil)propiloksifosfinil]amino]-2-feniletiķskābes; 2-[[(2-naftil)propiloksifosfinil]amino]-2-feniletiķskābes;

2-[[(1 -naftil)butiloksifosfinil]amino]-2-feniletiķskābes;

25 2-[[(2-naftil)butiloksifosfinil]amino]-2-feniletiķskābes; 2-[[fenilprop-2-eniloksifosfinil]amino]-2-feniletiķskābes; 2-[[benziloksifosfinil]amino]-2-rnetiletiķskābes; 2-[[benziloksifosfinil]amino]-2-etiletiķskābes; 2-[[benziloksifosfinil]amino]-2-propiletiķskābes;

30 2-[[benziloksifosfinil]amino]-2-butiletiķskābes;

2-[[benziloksifosfinil]amino]-2-cikloheksiletiķskābes;

2-[[benziloksifosfinil]amino]-2-(cikloheksil)metiletiķskābes;

2-[[benziloksifosfinil]amino]-2-feniletiķskābes;

2-[[benziloksifosfinil]amino]-2-benziletiķskābes;

2-[[benziloksifosfinil]amino]-2-feniletiletiķskābes;

2-[[benziloksifosfinil]amino]-2-fenilpropiletiķskābes;

2-[[benziloksifosfinil]amino]-2-fenilbutiletiķskābes;

2-[[benziloksifosfinil]aminoJ-2-(2,3₁4-trimetoksifenil)etiķskābes;

2-[[benziloksifosfinil]amino]-2-(1-naftil)etiķskābes;

2-[[benziloksifosfinil]amino]-2-(2-naftil)etiķskābes;

2-[[benziloksifosfinil]amino]-2-(1-naftil)metiletiķskābes;

2-[[benziloksifosfinil]amino]-2-(2-naftil)metiletiķskābes;

2-[[benziloksifosfinil]amino]-2-(1 -naftil)etiletiķskābes;

2-[[benziloksifosfinil]amino]-2-(2-naftil)etiletiķskābes;

2-[[benziloksifosfinil]amino]-2-(1-naftil)propiletiķskābes;

2-[[benziloksifosfinil]amino]-2-(2-naftil)propiletiķskābes;

2-[[benziloksifosfinil]amino]-2-(1-naftil)butiletiķskābes;

2-[[benziloksifosfinil]amino]-2-(2-naftil)butiletiķskābes;

2-[[benziloksifosfinil]amino]-2-fenilprop-2-eniletiķskābes;

2-[(metiloksifosfinil)amino]adipīnskābes;

2-[(benziloksifosfinil)amino]adipīnskābes;

2-[(metiloksifosfinil)amino]pimelīnskābes;

2-[(benziloksifosfinil)amino]pimelīnskābes;

2-[(metiloksifosfinil)amino]heksāndikarbonskābes;

2-[(benziloksifosfinil)amino]heksāndikarbonskābes;

2-[(metiloksifosfinil)amino]azelaīnskābes;

2-[(benziloksifosfinil)amino]azelaīnskābes;

2-[(metiloksifosfinil)amino]sebacīnskābes;

2- [(benziloksifosfinil)amino]sebacīnskābes;

3- [[(2-piridil)metiloksifosfinil]amino]glutārskābes;

3-[[(3-piridil)metiloksifosfinil]amino]glutārskābes;

3-[[(4-pindil)metiloksifosfinil]amino]glutārskābes;

3-[[(3-piridil)etiloksifosfinil]amino]glutārskābes;

3-[[(3-piridil)propiloksifosfinil]amino]glutārskābes;

3-[[(tetrahidrofuranil)metiloksifosfinil]amino]glutārskābes;

3-[[(tetrahidrofuranil)etiloksifosfinil]amino]glutārskābes;

3-[[(tetrahidrofuranil)propiloksifosfinil]amino]glutārskābes;

3-[[(2-indolil)metiloksifosfinil]amino]glutārskābes;

3-[[(3-indolil)metiloksifosfinil]amino]glutārskābes;

3-[[(4-indolil)metiloksifosfinil]amino]glutārskābes;

3-[[(3-indolil)etiloksifosfinil]amino]glutārskābes;

3-[[(3-indolil)propiloksifosfinil]amino]glutārskābes;

3-[[(2-tienil)metiloksifosfinil]amino]glutārskābes;

3-[[(3-tienil)metiloksifosfinil]amino]glutārskābes;

3-[[(4-tieniI)metīloksifosfinil]amino]glutārskābes;

3-[[(3-tienil)etiloksifosfinil]amino]glutārskābes;

3-[[(3-tienil)propiloksifosfinil]amino]glutārskābes;

2-[[(2-piridil)metiloksifosfinil]amino]-2-feniletiķskābes;

2-[[(3-piridil)metiloksifosfinil]amino]-2-feniletiķskābes;

2-[[(4-piridil)metiloksifosfinil]amino]-2-feniletiķskābes;

2-[[(3-piridil)etiloksifosfinil]amino]-2-feniletiķskābes;

2-[[(3-piridil)propiloksifosfinil]amino]-2-feniletiķskābes;

2-[[(tetrahidrofuranil)metiloksifosfinil]amino]-2-feniletiķskābes;

2-[[(tetrahidrofuranil)etiloksifosfinil]amino]-2-feniletiķskābes;

2-[[(tetrahidrofuranil)propiloksifosfinil]amino]-2-feniletiķskābes;

2-[[(2-indolil)metiloksifosfinil]amino]-2-feniletiķskābes;

2-[[(3-indolil)metiloksifosfinil]amino]-2-feniletiķskābes;

2-[[(4-indolil)metiloksifosfinil]amino]-2-feniletiķskābes;

2-[[(3-indolil)etiloksifosfinil]amino]-2-feniletiķskābes;

2-[[(3-indolil)propiloksifosfinil]amino]-2-feniletiķskābes;

2-[[(2-tienil)metiloksifosfinil]amino]-2-feniletiķskābes;

2-[[(3-tienil)metiloksifosfinil]amino]-2-feniletiķskābes;

2-[[(4-tienii)metiloksifosfinil]amino]-2-feniietiķskābes;

2-[[(3-tienil)etiloksifosfinil]amino]-2-feniletiķskābes;

2-[[(3-tienil)propiloksifosfinil]amino]-2-feniletiķskābes;

2-[[benziloksifosfinil]amino]-2-(2-piridil)metiletiķskābes;

2-[[benziloksifosfinil]amino]-2-(3-piridil)metiletiķskābes;

2-[[benziloksifosfinil]amino]-2-(4-piridil)metiletiķskābes;

2-[[benziloksifosfinil]amino]-2-(3-piridil)etiletiķskābes;

2-[[benziIoksifosfinil]amino]-2-(3-piridil)propiletiķskābes;

2-[[benziloksifosfinil]amino]-2-(tetrahidrofuranil)metiletiķskābes;

2-[[benziloksifosfinil]amino]-2-(tetrahidrofuranil)etiletiķskābes;

2-[[benziloksifosfinil]amino]-2-(tetrahidrofuranil)propiletiķskābes;

2-[[benziloksifosfinil]amino]-2-(2-indolil)metiletiķskābes;

2-[[benziloksifosfinil]amino]-2-(3-indolil)metiletiķskābes;

2-[[benziloksifosfinil]amino]-2-(4-indolil)metiletiķskābes;

2-[[benziloksifosfinil]amino]-2-(3-indolil)etiletiķskābes;

2-[[benziloksifosfinil]amino]-2-(3-indolil)propiletiķskābes;

2-[[benziloksifosfinil]amino]-2-(2-tienil)metiletiķskābes;

2-[[benziloksifosfinil]amino]-2-(3-tienil)metiletiķskābes;

2-[[benziloksifosfinil]amino]-2-(4-tienil)metiletiķskābes;

2-[[benziloksifosfinil]amino]-2-(3-tienil)etiletiķskābes;

2-[[benziloksifosfinil]amino]-2-(3-tienil)propiletiķskābes;

un farmaceitiski pieņemama sāls, hidrāta un vielu maisījuma.

17. Pielietojums saskaņā ar 15. punktu, kas atšķiras ar to, ka NAALADāzes inhibitoru izvēlas no grupas, kas sastāv no:

2-[(benziloksifosfinil)amino]glutārskābes;

2-[(feniloksifosfinil)amino]glutārskābes;

2-[[((oksi)fenilmetil)oksifosfinil]amino]glutārskābes;

2-[(butiloksifosfinil)amino]glutārskābes;

2-[[(3-metilbenzil)oksifosfinil]amino]glutārskābes;

2-[(3-fenilpropiloksifosfinil)amino]glutārskābes;

2-[[(4-fluorfenil)oksifosfinil]amino]glutārskābes;

2-[(metiloksifosfinil)amino]glutārskābes;

2-[(feniletiloksifosfinil)amino]glutārskābes;

2-[[(4-metilbenzil)oksifosfinil]amino]glutārskābes;

2-[[(4-fluorbenzil)oksifosfinil]amino]glutārskābes;

2-[[(4-metoksibenzil)oksifosfinil]amino]glutārskābes;

2-[(fosfono)amino]glutārskābes;

2-[[(3-trifluormetilbenzil)oksifosfinil]amino]glutārskābes;

2-[[(2-fluorbenzil)oksifosfinil]amino]glutārskābes;

2-[[(pentafluorbenzil)oksifosfinil]amino]glutārskābes;

un farmaceitiski pieņemama sāls, hidrāta vai vielu maisījuma.

18. Pielietojums saskaņā ar 8. punktu, kas atšķiras ar to, ka Rļ vai R₂ ir heterocikliska grupa un X ir CH₂-grupa.

19. Pielietojums saskaņā ar 18. punktu, kas atšķiras ar to, ka NAALADāzes inhibitoru izvēlas no grupas, kas sastāv no: 2-[[(2-piridil)oksifosfinil]metil]glutārskābes;

2-[[(3-piridil)oksifosfinil]metil]glutārskābes;

2-[[(4-piridil)oksifosfinil]metil]glutārskābes;

2-[[(tetrahidrofuranil)oksifosfinil]metil]glutārskābes;

2-[[(2-indolil)oksifosfinil]metil]glutārskābes;

2-[[(3-indolil)oksifosfinil]metil]glutārskābes;

2-[[(4-indolil)oksifosfiniI]metil]gIutārskābes;

2-[[(2-tienil)oksifosfinil]metil]glutārskābes;

2-[[(3-tienil)oksifosfinil]metil]glutārskābes;

2- [[(4-tienil)oksifosfinil]metil]glutārskābes;

3- [(2-piridil)oksifosfinil]-2-fenilpropionskābes;

3-[(3-piridil)oksifosfinil]-2-fenilpropionskābes;

3-[(4-piridil)oksifosfinil]-2-fenilpropionskābes;

3-[(tetrahidrofuranil)oksifosfinil]-2-fenilpropionskābes;

3-[(2-indolil)oksifosfinil]-2-fenilpropionskābes;

3-[(3-indolil)oksifosfinil]-2-fenilpropionskābes;

3-[(4-indolil)oksifosfinil]-2-fenilpropionskābes;

3-[(2-tienil)oksifosfinil]-2-fenilpropionskābes;

3-[(3-tienil)oksifosfinil]-2-fenilpropionskābes;

3-[(4-tienil)oksifosfinilj-2-fenilpropionskābes;

3-(benziloksifosfinil)-2-(2-piridil)propionskābes;

3-(benziloksifosfinil)-2-(3-piridil)propionskābes;

3-(benziloksifosfinil)-2-(4-piridil)propionskābes;

3-(benziloksifosfinil)-2-(tetrahidrofuranil)propionskābes;

3-(benziloksifosfinil)-2-(2-indolil)propionskābes;

3-(benziloksifosfinil)-2-(3-indolil)propionskābes;

3-(benziloksifosfinil)-2-(4-indolil)propionskābes;

3-(benziloksifosfinil)-2-(2-tienil)propionskābes;

3-(benziloksifosfinil)-2-(3-tienil)propionskābes;

3-(benziloksifosfinil)-2-(4-tienil)propionskābes;

un farmaceitiski pieņemama sāls, hidrāta vai vielu maisījuma.

20. Pielietojums saskaņā ar 8. punktu, kas atšķiras ar to, ka R₃ vai R₂ ir heterocikliska grupa un X ir skābekļa atoms.

21. Pielietojums saskaņā ar 20. punktu, kas atšķiras ar to, ka NAALADāzes inhibitoru izvēlas no grupas, kas sastāv no: 2-[[(2-piridil)oksifosfinil]oksi]glutārskābes;

2-[[(3-piridil)oksifosfinil]oksi]glutārskābes;

2-[[(4-piridil)oksifosfinil]oksi]glutārskābes;

2-[[(tetrahidrofuranil)oksifosfinil]oksi]glutārskābes;

2-[[(2-indolil)oksifosfinil]oksi]glutārskābes;

2-[[(3-indolil)oksifosfinil]oksi]glutārskābes;

2-[[(4-indolil)oksifosfinil]oksi]glutārskābes;

2-[[(2-tienil)oksifosfinil]oksi]glutārskābes;

2-[[(3-tienil)oksifosfinil]oksi]glutārskābes;

2-[[(4-tienil)oksifosfinil]oksi]glutārskābes;

2-[[(2-piridil)oksifosfinil]oksi]-2-feniletiķskābes;

2-[[(3-piridil)oksifosfinil]oksi]-2-feniletiķskābes;

2-[[(4-piridil)oksifosfinil]oksi]-2-feniletiķskābes;

2-[[(tetrahidofuranil)oksifosfinil]oksi]-2-feniletiķskābes;

2-[[(2-indolil)oksifosfinil]oksi]-2-feniletiķskābes;

2-[[(3-indolil)oksifosfinil]oksi]-2-feniletiķskābes;

2-[[(4-indolil)oksifosfinil]oksi]-2-feniletiķskābes;

2-[[(2-tienil)oksifosfinil]oksi]-2-feniletiķskābes;

2-[[(3-tienil)oksifosfinil]oksi]-2-feniletiķskābes;

2-[[(4-tienil)oksifosfinil]oksi]-2-feniletiķskābes;

2-[[benziloksifosfinil]oksi]-2-(2-piridil)etiķskābes;

2-[[benziloksifosfinil]oksi]-2-(3-piridil)etiķskābes;

2-[[benziloksifosfinil]oksi]-2-(4-piridil)etiķskābes;

2-[[benziloksifosfinil]oksi]-2-(tetrahidrofuranil)etiķskābes;

2-[[benziloksifosfinil]oksi]-2-(2-indolil)etiķskābes;

2-[[benziloksifosfinil]oksi]-2-(3-indolil)etiķskābes;

2-[[benziloksifosfinil]oksi]-2-(4-indolil)etiķskābes;

2-[[benziloksifosfinil]oksi]-2-(2-tienil)etiķskābes;

2-[[benziloksifosfinil]oksi]-2-(3-tienil)etiķskābes;

2-[[benziloksifosfinil]oksi]-2-(4-tienil)etiķskābes;

un farmaceitiski pieņemama sāls, hidrāta vai vielu maisījuma.

22. Pielietojums saskaņā ar 8. punktu, kas atšķiras ar to, ka R, vai R₂ ir heterocikliska grupa un X ir NRļ-grupa.

23. Pielietojums saskaņā ar 22. punktu, kas atšķiras ar to, ka NAALADāzes inhibitoru izvēlas no grupas, kas sastāv no: 2-[[(2-piridil)oksifosfinil]amino]glutārskābes;

2-[[(3-piridil)oksifosfinil]amino]glutārskābes;

2-[[(4-piridil)oksifosfinil]amino]glutārskābes;

2-[[(tetrahidrofuranil)oksifosfinil]amino]glutārskābes;

2-[[(2-indolil)oksifosfinii]amino]glutārskābes;

2-[[(3-indolil)oksifosfinil]amino]glutārskābes;

2-[[(4-indolil)oksifosfinil]amino]glutārskābes;

2-[[(2-tienil)oksifosfinil]amino]glutārskābes;

2-[[(3-tienil)oksifosfinil]amino]glutārskābes;

2-[[(4-tienil)oksifosfinil]amino]glutārskābes;

2-[[(2-piridil)oksifosfinil]amino]-2-feniletiķskābes;

2-[[(3-piridil)oksifosfinil]amino]-2-feniletiķskābes;

2-[[(4-piridil)oksifosfinil]amino]-2-feniletiķskābes;

2-[[(tetrahidrofuranil)oksifosfinil]amino]-2-feniletiķskābes;

2-[[(2-indolil)oksifosfinil]amino]-2-feniletiķskābes;

2-[[(3-indolil)oksifosfinil]amino]-2-feniletiķskābes;

2-[[(4-indolil)oksifosfinil]amino]-2-feniletiķskābes;

2-[[(2-tienil)oksifosfinil]amino]-2-feniletiķskābes;

2-[[(3-tienil)oksifosfinil]amino]-2-feniletiķskābes;

2-[[(4-tienil)oksifosfinil]amino]-2-feniletiķskābes;

2-[[benziloksifosfinil]amino]-2-(2-piridil)etiķskābes;

2-[[benziloksifosfinil]amino]-2-(3-piridil)etiķskābes;

2-[[benziloksifosfinil]amino]-2-(4-piridil)etiķskābes;

2-[[benziloksifosfinil]amino]-2-(tetrahidrofuranil)etiķskābes;

2-[[benziloksifosfinil]amino]-2-(2-indolil)etiķskābes;

2-[[benziloksifosfinil]amino]-2-(3-indolil)etiķskābes;

2-[[benziloksifosfinil]amino]-2-(4-indolil)etiķskābes;

2-[[benziloksifosfinil]amino]-2-(2-tienil)etiķskābes;

2-[[benziloksifosfinil]amino]-2-(3-tienil)etiķskābes;

2-[[benziloksifosfinil]amino]-2-(4-tienil)etiķskābes;

un farmaceitiski pieņemama sāls, hidrāta vai vielu maisījuma.

24. NAALADāzes inhibitora pielietojums audzēja šūnu augšanas inhibēšanai dzīvniekiem, kuri cieš no audzēja šūnu augšanas.

25. Pielietojums saskaņā ar 24. punktu, kas atšķiras ar to, ka audzējs ir prostatas adenokarcinoma.

26. Pielietojums saskaņā ar 24. punktu, kas atšķiras ar to, ka NAALADāzes inhibitoru izvēlas no grupas, kas sastāv no: glutamāta atvasinājuma oksifosfinilatvasinājuma; skābā peptīda analoga; konformācijas ziņā traucētas glutamāta imitētājvielas; un šo vielu maisījumiem.

27. Pielietojums saskaņā ar 26. punktu, kas atšķiras ar to, ka NAALADāzes inhibitors ir glutamāta atvasinājuma oksifosfinilatvasinājums.

28. Pielietojums saskaņā ar 24. punktu, kas atšķiras ar to, ka NAALADāzes inhibitoru lieto kopā ar papildu terapeitisku līdzekli, kuru izvēlas no grupas, kas sastāv no: terapeitiskiem hormoniem, ķimioterapeitiskiem hormoniem, anti-angioģenēzes līdzekļiem, ar radioaktīvo izotopu iezīmētiem savienojumiem un šo vielu maisījumiem.

29. Pielietojums saskaņā ar 24. punktu, kas atšķiras ar to, ka vēzis ir audzējs no grupas: ACTH producējošs audzējs, akūta limfocitārā leikēmija, akūta nelimfocitārā leikēmija, virsnieru dziedzera garozas vēzis, urīnpūšļa vēzis, galvas smadzeņu vēzis, krūts dziedzera vēzis, cervikāla vēzis, hroniska limfoleikēmija, hroniska mieloleikēmija, taisnās zarnas vēzis, ādas T-šūnu limfoma, endometrija vēzis, barības vada vēzis, Jūinga sarkoma, ultspūšia vēzis, mataino šūnu leikēmija, galvas un kakla vēzis, Hodžkina limfoma, Kapoši sarkoma, nieru vēzis, aknu vēzis, plaušu vēzis, plaušu vēzis (smalkšūnu un/vai lielšūnu), ļaundabīgā peritoneālā efūzija, ļaundabīgā pleirālā efūzija, melanoma, mezotelioma, multiplā mieloma, neiroblastoma, ne-Hodžkina limfoma, osteosarkoma, olnīcu vēzis, olnīcu (dzimumšūnu) vēzis, aizkuņģa dziedzera vēzis, dzimumlocekļa vēzis, prostatas vēzis, retinoblastoma, ādas vēzis, mīksto audu vēzis, zvīņveida šūnu karcinomas, kuņģa vēzis, sēklinieka vēzis, vairogdziedzera vēzis, trofoblasta neoplazmas, dzemdes vēzis, maksts vēzis, vulvas vēzis un Vilmsa audzējs.

30. Pielietojums saskaņā ar 24. punktu, kas atšķiras ar to, ka audzējs ir prostatas adenokarcinoma.

31. Pielietojums saskaņā ar 24. punktu, kas atšķiras ar to, ka audzēju izvēlas no grupas, kas sastāv no: galvas smadzeņu vēža, virsnieru dziedzera garozas vēža, nieru vēža un sēklinieka vēža.

32. Pielietojums saskaņā ar 24. punktu, kas atšķiras ar to, ka NAALADāzes inhibitorā ietilpst savienojums ar sekojošu formulu:

OH

Formula I,

R₂ ir C, - C₉ alkilgrupa ar taisnu vai sazarotu virkni, C₂ - C₉alkenilgrupa ar taisnu vai sazarotu virkni, C₃ - C₈cikloalkil-, C₅ - C₇ cikloalkenil- vai Ar,- grupa; šī alkil-, alkenil-, cikloalkil-, cikloalkenil- vai arilgrupa var būt aizvietota ar karbonskābi;

minētās alkil-, alkenil-, cikloalkil-, cikloalkenil- vai arilgrupas var būt aizvietotas ar C₃ - C₈ cikloalkil-, C₃- vai C₅ cikloalkil-, C₅ - C₇ cikloalkenil-, C, - C₄ alkil-, C, - C₄ alkenilgrupām, halogēna atomu, oksi-, karboksi- nitro,trifiuormetilgrupām, C, - C₆ alkil- vai C, - C₆ alkenilgrupu ar taisnu vai sazarotu virkni, C, - C₄ alkoksi-, C, -C₄ alkeniloksi-, fenoksi-, benziloksi-, amino- vai Ar,-grupu un kur Ar,-grupu izvēlas no grupas, kura sastāv no

1- naftil-, 2-naftil-, 2-indolil-, 3-indolil-, 4-indolil-, 2-furil-, 3-furil-, tetrahidrofuranil-, 2-tienil-, 3-tienil-, 4-tienil-, 2-, 3-, vai 4-piridil- vai fenilgrupas, kas satur no viena līdz pieciem aizvietotājiem, kurus neatkarīgi izvēlas no grupas, kas sastāv no ūdeņraža atoma, halogēna atoma, oksi-, karboksi-, nitro-, trifluormetil-, C, - C₆ alkil- vai C, - C₆alkenilgrupas ar taisnu vai sazarotu virkni, C, - C₄ alkoksi- vai C, - C₄ alkeniloksi-, fenoksi-, benziloksi- un aminogrupām; vai šī savienojuma farmaceitiski pieņemami sāļi, hidrāti vai vielu maisījumi.

33. Pielietojums saskaņā ar 32. punktu, kas atšķiras ar to, ka R, un R₂ ir alifātiskas grupas ar taisnu vai sazarotu virkni vai karbocikliskas grupas un X ir CH₂-grupa.

34. Pielietojums saskaņā ar 33. punktu, kas atšķiras ar to, ka NAALADāzes inhibitoru izvēlas no grupas, kas sastāv no:

2- [[metiloksifosfinil]metil]glutārskābes;

2-[[etiloksifosfinil]metil]glutārskābes;

2-[[propiloksifosfinil]metil]glutārskābes;

2-[[butiloksifosfinil]metil]glutārskābes;

2-[[cikloheksiloksifosfinil]metil]glutārskābes;

2-[[(cikloheksil)metiloksifosfinil]metil]glutārskābes;

2-[[feniloksifosfinil]metil]glutārskābes;

2-[[benziloksifosfinil]metil]glutārskābes;

2-[[feniletiloksifosfinil]metil]glutārskābes;

2-[[fenilpropiloksifosfinil]metil]glutārskābes;

2-[[fenilbutiloksifosfinil]metil]glutārskābes;

2-[[(4-metilbenzil)oksifosfinil]metil]glutārskābes;

2-[[(4-fluorbenzil)oksifosfinil]metil]glutārskābes;

2-[[(2-fluorbenzil)oksifosfinil]metil]glutārskābes;

2-[[(pentafluorbenzil)oksifosfinil]metil]glutārskābes;

2-[[(metoksibenzil)oksifosfinil]metil]glutārskābes;

2-[[(2,3,4-trimetoksifenil)oksifosfinil]metil]glutārskābes;

2-[[(1 -naftil)oksifosfinil]metil]glutārskābes;

2-[[(2-naftil)oksifosfinil]metil]glutārskābes;

2-[[(1 -naftil)metiloksifosfinil]metil]glutārskābes; 2-[[(2-naftil)metiloksifosfinil]metil]glutārskābes;

2-[[(1 -naftil)etiloksifosfinil]metil]glutārskābes; 2-[[(2-naftil)etiloksifosfinil]metil]glutārskābes; 2-[[(1-naftil)propiloksifosfinil]metil]glutārskābes; 2-[[(2-naftil)propiloksifosfinil]metil]glutārskābes;

2-[[(1 -naftil)butiloksifosfinil]metil]glutārskābes;

2-[[(2-naftil)butiloksifosfinil]metil]glutārskābes;

2-[[(fenilprop-2-enil)oksifosfinil]metil]glutārskābes;

2-[[(2-fluorbenzil)oksifosfinil]metil]glutārskābes;

2-[[(4-fluorfenil)oksifosfinil]metil]glutārskābes;

2-[[((oksi)feniimetiI)oksifosfinil]metil]glutārskābes;

2-[[(3-metiIbenzil)oksifosfinif]metil]glutārskābes;

2-(fosfonometil)glutārskābes;

2- [[(3-trifluormetilbenzil)oksifosfinil]metil]glutārskābes;

3- (metiloksifosfinil)-2-fenilpropionskābes; 3-(etiloksifosfinil)-2-fenilpropionskābes; 3-(propiloksifosfinil)-2-fenilpropionskābes; 3-(butiloksifosfinil)-2-fenilpropionskābes;

3-(cikloheksiloksifosfinil)-2-fenilpropionskābes;

3-((cikloheksil)metiloksifosfinil)-2-fenilpropionskābes;

3-(feniloksifosfinil)-2-fenilpropionskābes;

3-(benziloksifosfinii)-2-fenilpropionskābes;

3-(feniletiloksifosfinil)-2-fenilpropionskābes;

3-(fenilpropiloksifosfinil)-2-fenilpropionskābes;

3-(fenilbutiloksifosfinil)-2-fenilpropionskābes;

3-((2,3,4-trimetoksifenil)-3-oksifosfinil)-2-fenilpropionskābes; 3-((1 -naftil)oksifosfinil)-2-fenilpropionskābes; 3-((2-naftil)oksifosfinil)-2-fenilpropionskābes;

3-((1-naftil)metiloksifosfinil)-2-fenilpropionskābes; 3-((2-naftil)metiloksifosfinil)-2-fenilpropionskābes;

3-((1-naftil)etiloksifosfinil)-2-fenilpropionskābes; 3-((2-naftil)etiloksifosfinil)-2-fenilpropionskābes;

3-((1 -naftil)propiloksifosfinil)-2-fenilpropionskābes; 3-((2-naftil)propiloksifosfinil)-2-feniIpropionskābes;

3-((1-naftil)butiloksifosfinil)-2-fenilpropionskābes;

3-((2-naftil)butiloksifosfinil)-2-fenilpropionskābes;

3-(fenilprop-2-eniloksifosfinil)-2-fenilpropionskābes;

2-[(benziloksifosfinil)metil]glutārskābes;

2-[(metiloksifosfinil)metil]adipīnskābes;

2-[(benziloksifosfinil)metil]adipīnskābes;

2-[(metiloksifosfinil)metil]pimelīnskābes;

2-[(benziloksifosfinil)metil]pimelīnskābes;

2-[(metiloksifosfinil)metil]heksāndikarbonskābes;

2-[(benziloksifosfinil)metil]heksāndikarbonskābes;

2-[(metiloksifosfinil)metil]azelaīnskābes;

2-[(benziloksifosfinil)metil]azelaīnskābes;

2-[(metiloksifosfinil)metil]sebacīnskābes;

2- [(benziloksifosfinil)metil]sebacīnskābes;

3- (benziloksifosfinil)-2-metilpropionskābes;

3-(benziloksifosfinil)-2-etilpropionskābes;

3-(benziloksifosfinil)-2-propilpropionskābes;

3-(benziloksifosfinil)-2-butilpropionskābes;

3-(benziloksifosfinil)-2-cikloheksilpropionskābes;

3-(benziloksifosfinil)-2-(cikloheksil)metilpropionskābes;

5 3-(benziloksifosfinil)-2-fenilpropionskābes; 3-(benziloksifosfinil)-2-benzilpropionskābes; 3-(benziloksifosfinil)-2-feniletilpropionskābes; 3-(benziloksifosfinil)-2-fenilpropilpropionskābes; 3-(benziloksifosfinil)-2-fenilbutilpropionskābes;

10 3-(benziloksifosfinil)-2-(2,3,4-trimetoksifenil)propionskābes; 3-(benziloksifosfinil)-2-(1-naftil)propionskābes; 3-(benziloksifosfinil)-2-(2-naftil)propionskābes; 3-(benziloksifosfinil)-2-(1-naftil)metilpropionskābes; 3-(benziloksifosfinil)-2-(2-naftil)metilpropionskābes;

15 3-(benzi loksifosfin i 1)-2-( 1 -naftil)etilpropionskābes;

3-(benziloksifosfinil)-2-(2-naftil)etilpropionskābes; 3-(benziloksifosfinil)-2-(1-naftil)propilpropionskābes; 3-(benziloksifosfinil)-2-(2-naftil)propilpropionskābes; 3-(benziloksifosfinil)-2-(1-naftil)butilpropionskābes;

20 3-(benziloksifosfinil)-2-(2-naftil)butilpropionskābes; 3-(benziloksifosfinil)-2-fenilprop-2-enilpropionskābes; 2-[[(2-piridil)metiloksifosfinil]metilJglutārskābes; 2-[[(3-piridil)metiloksifosfinil]metil]glutārskābes; 2-[[(4-piridil)metiloksifosfinil]metii]glutārskābes;

25 2-[[(3-piridil)etiloksifosfinil]metil]glutārskābes; 2-[[(3-piridil)propiloksifosfiniljmetil]glutārskābes; 2-[[(tetrahidrofuranil)metiloksifosfinilļmetil]glutārskābes; 2-[[(tetrahidrofuranil)etiloksifosfiniljmetil]glutārskābes; 2-[[(tetrahidrofuranil)propiloksifosfinil]metil]glutārskābes;

30 2-[[(2-indolil)metiloksifosfinil]metil]glutārskābes; 2-[[(3-indolil)metiloksifosfinil]metil]glutārskābes; 2-[[(4-indolil)metiloksifosfinil]metil}glutārskābes;

2-[[(3-indolil)etiloksifosfiniI]metil]glutārskābes;

2-[[(3-indolil)propiloksifosfinil]metil]glutārskābes;

2-[[(2-tienil)metiloksifosfinil]metil]glutārskābes;

2-[[(3-tienil)metiloksifosfinil]metil]glutārskābes;

2-[[(4-tienil)metiloksifosfinil]metil]glutārskābes;

2-[[(3-tienil)etiloksifosfinil]metil]glutārskābes;

2- [[(3-tienil)propiloksifosfinil]metil]glutārskābes;

3- [(2-piridil)metiloksifosfinil]-2-fenilpropionskābes; 3-[(3-piridil)metiloksifosfinil]-2-fenilpropionskābes; 3-[(4-piridil)metiloksifosfinil]-2-fenilpropionskābes; 3-[(3-piridil)etiloksifosfinil]-2-fenilpropionskābes; 3-[(3-piridil)propiloksifosfinil]-2-fenilpropionskābes; 3-[(tetrahidrofuranil)metiloksifosfinil]-2-fenilpropionskābes; 3-[(tetrahidrofuranil)etiloksifosfinil]-2-fenilpropionskābes; 3-[(tetrahidrofuranil)propiloksifosfinil]-2-fenilpropionskābes; 3-[(2-indolil)metiloksifosfinilj-2-fenilpropionskābes; 3-[(3-indolil)metiloksifosfinil]-2-fenilpropionskābes; 3-[(4-indolil)metiloksifosfinil]-2-fenilpropionskābes; 3-[(3-indolil)etiloksifosfinil]-2-fenilpropionskābes; 3-[(3-indolil)propiloksifosfinil]-2-fenilpropionskābes; 3-[(2-tienil)metiloksifosfinil]-2-fenilpropionskābes; 3-[(3-tienil)metiloksifosfinil]-2-fenilpropionskābes; 3-[(4-tienil)metiloksifosfinil]-2-fenilpropionskābes; 3-[(3-tienil)etiloksifosfinil]-2-fenilpropionskābes; 3-[(3-tienil)propiloksifosfinil]-2-fenilpropionskābes; 3-(benziloksifosfinil)-2-(2-piridil)metilpropionskābes; 3-(benziloksifosfinil)-2-(3-piridil)metilpropionskābes; 3-(benziloksifosfinil)-2-(4-piridil)metilpropionskābes; 3-(benziloksifosfinil)-2-(3-piridil)etilpropionskābes; 3-(benziloksifosfinil)-2-(3-piridil)propilpropionskābes; 3-(benziloksifosfinil)-2-(tetrahidrofuranil)metilpropionskābes; 3-(benziloksifosfinil)-2-(tetrahidrofuranil)etilpropionskābes;

3-(benziloksifosfinil)-2-(tetrahidrofuranil)propilpropionskābes;

3-(benziloksifosfinil)-2-(2-indolil)metilpropionskābes;

3-(benziloksifosfinil)-2-(3-indolil)metilpropionskābes;

3-(benziloksifosfinil)-2-(4-indolil)metilpropionskābes;

3-(benziloksifosfinil)-2-(3-indolil)etilpropionskābes;

3-(benziloksifosfinil)-2-(3-indolil)propilpropionskābes;

3-(benziloksifosfinil)-2-(2-tienil)metilpropionskābes;

3-(benziloksifosfinil)-2-(3-tienil)metilpropionskābes;

3-(benziloksifosfinil)-2-(4-tienil)metilpropionskābes;

3-(benziloksifosfinil)-2-(3-tienil)etilpropionskābes;

3-(benziloksifosfinil)-2-(3-tienil)propilpropionskābes;

un farmaceitiski pieņemama sāls, hidrāta vai vielu maisījuma.

35. Pielietojums saskaņā ar 33. punktu, kas atšķiras ar to, ka NAALADāzes inhibitoru izvēlas no grupas, kas sastāv no: 2-[(benziloksifosfinil)metil]glutārskābes;

2-[(feniloksifosfinil)metil]glutārskābes;

2-[[((oksi)fenilmetil)oksifosfinil]metil]glutārskābes;

2-[(butiloksifosfinil)metil]glutārskābes;

2-[[(3-metilbenzil)oksifosfinil]metil]glutārskābes;

2-[(3-fenilpropiloksifosfinil)metil]glutārskābes;

2-[[(4-fluorfenil)oksifosfinil]metil]glutārskābes;

2-[(metiloksifosfinil)metil]glutārskābes;

2-[(feniletiloksifosfinil)metil]glutārskābes;

2-[[(4-metilbenzil)oksifosfinil]metil]glutārskābes;

2-[[(4-fluorbenzil)oksifosfinil]metil]glutārskābes;

2-[[(4-metoksibenzil)oksifosfinil]metil]glutārskābes;

2-(fosfonometil)glutārskābes;

2-[[(3-trifluormetilbenzil)oksifosfinil]metil]glutārskābes;

2-[[(2-fluorbenzil)oksifosfinil]metil]glutārskābes;

2-[[(pentafluorbenzil)oksifosfinil]metil]glutārskābes;

un farmaceitiski pieņemama sāls, hidrāta vai vielu maisījuma.

36. Pielietojums saskaņā ar 32. punktu, kas atšķiras ar to, ka R, un R₂ ir alifātiskās grupas ar taisnu vai sazarotu virkni vai karbocikliskas grupas un X ir skābekļa atoms.

37. Pielietojums saskaņā ar 36. punktu, kas atšķiras ar to, ka NAALADāzes inhibitoru izvēlas no grupas, kas sastāv no: 2-[[metiloksifosfinil]oksi]glutārskābes;

2-[[etiloksifosfinil]oksi]glutārskābes;

2-[[propiloksifosfinil]oksi]glutārskābes;

2-[[butiloksifosfinil]oksi]glutārskābes;

2-[[cikloheksiloksifosfinil]oksi]glutārskābes;

2-[[(cikloheksil)metiloksifosfinil]oksi]glutārskābes;

2-[[feniloksifosfinil]oksi]glutārskābes;

2-[[benziloksifosfinil]oksi]glutārskābes;

2-[[feniletiIoksifosfinil]oksi]glutārskābes;

2-[[fenilpropiloksifosfinil]oksi]glutārskābes;

2-[[fenilbutiloksifosfinil]oksi]glutārskābes;

2-[[(4-metilbenzil)oksifosfinil]oksi]glutārskābes;

2-[[(4-fluorbenzil)oksifosfinil]oksi]glutārskābes;

2-[[(2-fluorbenzil)oksifosfinil]oksi]glutārskābes;

2-[[(pentafluorbenzil)oksifosfinil]oksi]glutārskābes;

2-[[(metoksibenzil)oksifosfinil]oksi]glutārskābes;

2-[[(2,3,4-trimetoksifenil)oksifosfinil]oksi]glutārskābes;

2-[[(1-naftil)oksifosfinil]oksi]glutārskābes;

2-[[(2-naftil)oksifosfinil]oksi]glutārskābes;

2-[[(1 -naftil)metiloksifosfinil]oksi]glutārskābes;

2-[[(2-naftil)metiloksifosfinil]oksi]glutārskābes;

2-[[(1 -naftil)etiloksifosfinil]oksi]glutārskābes;

2-[[(2-naftil)etiloksifosfinil]oksi]glutārskābes;

2-[[(1-naftil)propiloksifosfinil]oksi]glutārskābes;

2-[[(2-naftil)propiloksifosfinil]oksi]glutārskābes;

2-[[(1-naftil)butiloksifosfinil]oksi]glutārskābes;

2-[[(2-naftil)butiloksifosfinil]oksi]glutārskābes;

2-[[(fenilprop-2-enil)oksifosfinil]oksi]glutārskābes;

2-[[benziloksifosfinil]oksi]glutārskābes;

2-[[(2-fluorbenzil)oksifosfinil]oksi]glutārskābes;

2-[[(4-fluorfenil)oksifosfinil]oksi]glutārskābes;

2-[[((oksi)fenilmetil)oksifosfinil]metil]glutārskābes;

2-[[(3-metilbenzil)oksifosfinil]metiI]glutārskābes;

2-[(fosfono)oksi]glutārskābes;

2-[[(3-trifluormetilbenzil)oksifosfinil]oksi]glutārskābes;

2-[[metiloksifosfinil]oksi]-2-feniletiķskābes;

2-[[etiloksifosfinil]oksi]-2-feniletiķskābes;

2-[[propiloksifosfinil]oksi]-2-feniletiķskābes;

2-[[butiloksifosfinil]oksi]-2-feniletiķskābes;

2-[[cikloheksiloksifosfinil]oksi]-2-feniletiķskābes;

2-[[(cikloheksil)metiloksifosfinil]oksi]-2-feniletiķskābes;

2-[[feniioksifosfiniljoksi]-2-feniletiķskābes;

2-[[benziloksifosfinil]oksi]-2-feniletiķskābes;

2-[[feniletiloksifosfinil]oksi]-2-feniletiķskābes;

2-[[fenilpropiloksifosfinil]oksi]-2-feniletiķskābes;

2-[[feniibutiloksifosfinil]oksi]-2-feniletiķskābes;

2-[[(2,3,4-trimetoksifenil)-3-oksifosfinil]oksi]-2-feniletiķskābes;

2-[[(1 -naftil)oksifosfinil]oksi]-2-feniletiķskābes;

2-[[(2-naftil)oksifosfinil]oksi]-2-feniletiķskābes;

2-[[(1-naftil)metiloksifosfinil]oksi]-2-feniletiķskābes;

2-[[(2-naftil)metiioksifosfinil]oksi]-2-feniletiķskābes;

2-[[(1-naftil)etiloksifosfinil]oksi]-2-feniletiķskābes;

2-[[(2-naftil)etiloksifosfinil]oksi]-2-feniletiķskābes;

2-[[(1-naftil)propiloksifosfinil]oksi]-2-feniletiķskābes;

2-[[(2-naftil)propiloksifosfinil]oksi]-2-feniletiķskābes;

2-[[(1-naftil)butiloksifosfinil]oksi]-2-feniletiķskābes;

2-[[(2-naftil)butiloksifosfinil]oksi]-2-feniletiķskābes;

2-[[fenilprop-2-eniloksifosfinil]oksi]-2-feniletiķskābes;

2-[(metiloksifosfinil)oksi]adipīnskābes;

2-[(benziloksifosfinil)oksi]adipīnskābes;

2-[(metiloksifosfinil)oksi]pimelīnskābes;

2-[(benziloksifosfinil)oksi]pimelīnskābes;

2-[(metiloksifosfinil)oksi]heksāndikarbonskābes;

2-[(benziloksifosfinil)oksi]heksāndikarbonskābes;

2-[(metiloksifosfinil)oksi]azelaīnskābes;

2-[(benziloksifosfinil)oksi]azelaīnskābes;

2-[(metiloksifosfinil)oksi]sebacīnskābes;

2-[(benziloksifosfinil)oksi]sebacīnskābes;

2-[[benziloksifosfinil]oksi]-2-metiletiķskābes;

2-[[benziloksifosfinil]oksi]-2-etiletiķskābes;

2-[[benziloksifosfinil]oksi]-2-propiletiķskābes;

2-[[benziloksifosfinil]oksi]-2-butiletiķskābes;

2-[[benziloksifosfinil]oksi]-2-cikloheksiletiķskābes;

2-[[benziloksifosfinil]oksi]-2-(cikloheksil)metiletiķskābes;

2-[[benziloksifosfinil]oksi]-2-feniletiķskābes;

2-[[benziloksifosfinil]oksi]-2-benziletiķskābes;

2-[[benziloksifosfinil]oksi]-2-feniletiletiķskābes;

2-[[benziloksifosfinil]oksi]-2-fenilpropiletiķskābes;

2-[[benziloksifosfinil]oksi]-2-fenilbutiletiķskābes;

2-[[benziloksifosfinil]oksi]-2-(2,3,4-trimetoksifenil)etiķskābes;

2-[[benziloksifosfinil]oksi]-2-(1-naftil)etiķskābes;

2-[[benziloksifosfinil]oksi]-2-(2-naftil)etiķskābes;

2-[[benziloksifosfinil]oksi]-2-(1 -naftil)metiletiķskābes;

2-[[benziloksifosfinil]oksi]-2-(2-naftil)metiletiķskābes;

2-[[benziloksifosfinil]oksi]-2-(1-naftil)etiletiķskābes;

2-[[benziloksifosfinil]oksi]-2-(2-naftil)etiletiķskābes;

2-[[benziloksifosfinil]oksi]-2-(1 -naftil)propiletiķskābes;

2-[[benziloksifosfinil]oksi]-2-(2-naftil)propiletiķskābes;

2-[[benziloksifosfinil]oksi]-2-(1 -naftil)butiletiķskābes;

2-[[benziloksifosfinil]oksi]-2-(2-naftil)butiletiķskābes;

2-[[benziloksifosfinil]oksi]-2-fenilprop-2-eniletiķskābes;

2-[[(2-piridil)metiloksifosfinil]oksi]glutārskābes;

2-[[(3-piridil)metiloksifosfinil]oksi]glutārskābes;

2-[[(4-piridil)metiloksifosfinil]oksi]glutārskābes;

2-[[(3-piridil)etiloksifosfinil]oksi]glutārskābes;

2-[[(3-piridil)propiloksifosfinil]oksi]glutārskābes;

2-[[(tetrahidrofuranil)metiloksifosfinil]oksi]glutārskābes;

2-[[(tetrahidrofuranil)etiloksifosfinil]oksi]glutārskābes;

2-[[(tetrahidrofuranil)propiloksifosfinil]oksi]glutārskābes;

2-[[(2-indolil)metiloksifosfinil]oksi]glutārskābes;

2-[[(3-indolil)metiloksifosfinil]oksi]glutārskābes;

2-[[(4-indolil)metiloksifosfinil]oksi]glutārskābes;

2-[[(3-indolil)etiloksifosfinil]oksi]glutārskābes;

2-[[(3-indolil)propiloksifosfinil]oksi]glutārskābes;

2-[[(2-tienil)metiloksifosfinil]oksi]glutārskābes;

2-[[(3-tienil)metiloksifosfinil]oksi]glutārskābes;

2-[[(4-tienil)metiloksifosfinil]oksi]glutārskābes;

2-[[(3-tienii)etiloksifosfinil]oksi]glutārskābes;

2-[[(3-tienil)propiloksifosfinil]oksi]glutārskābes;

2-[[(2-piridil)metiloksifosfinil]oksi]-2-feniletiķskābes;

2-[[(3-piridil)metiloksifosfinil]oksi]-2-feniletiķskābes;

2-[[(4-piridil)metiloksifosfinil]oksi]-2-feniletiķskābes;

2-[[(3-piridil)etiloksifosfinil]oksi]-2-feniletiķskābes;

2-[[(3-piridil)propiloksifosfinil]oksi]-2-feniletiķskābes;

2-[[(tetrahidrofuranil)metiloksifosfinil]oksi]-2-feniletiķskābes;

2-[[(tetrahidrofuranil)etiloksifosfinil]oksi]-2-feniletiķskābes;

2-[[(tetrahidrofuranil)propiloksifosfinil]oksi]-2-feniIetiķskābes;

2-[[(2-indolil)metiloksifosfinil]oksi]-2-feniletiķskābes;

2-[[(3-indolil)metiloksifosfinil]oksi]-2-feniletiķskābes;

2-[[(4-indolil)metiloksifosfinil]oksi]-2-feniletiķskābes;

2-[[(3-indolil)etiloksifosfinil]oksi]-2-feniletiķskābes;

2-[[(3-indolil)propiloksifosfinil]oksi]-2-feniletiķskābes;

2-[[(2-tienil)metiloksifosfinil]oksi]-2-feniletiķskābes;

2-[[(3-tienil)metiloksifosfinil]oksi]-2-feniletiķskābes;

2-[[(4-tienil)metiloksifosfinil]oksi]-2-feniletiķskābes;

2-[[(3-tienil)etiloksifosfinil]oksi]-2-feniletiķskābes;

2-[[(3-tienil)propiloksifosfinil]oksij-2-feniietiķskābes;

2-[[benziloksifosfinil]oksi]-2-(2-piridil)metiletiķskābes;

2-[[benziloksifosfinil]oksi]-2-(3-piridil)metiletiķskābes;

2-[[benziloksifosfinil]oksi]-2-(4-piridil)metiletiķskābes;

2-[[benziloksifosfinil]oksi]-2-(3-piridil)etiletiķskābes;

2-[[benziloksifosfinil]oksi]-2-(3-piridil)propiletiķskābes;

2-[[benziloksifosfinil]oksi]-2-(tetrahidrofuranil)metiletiķskābes;

2-[[benziloksifosfinil]oksi]-2-(tetrahidrofuranil)etiletiķskābes;

2-[[benziloksifosfinil]oksi]-2-(tetrahidrofuranil)propiletiķskābes;

2-[[benziloksifosfinii]oksi]-2-(2-indolil)metiletiķskābes;

2-[[benziloksifosfinil]oksi]-2-(3-indolil)metiletiķskābes;

2-[[benziloksifosfinil]oksi]-2-(4-indolil)metiletiķskābes;

2-[[benziloksifosfinil]oksi]-2-(3-indolil)etiletiķskābes;

2-[[benziIoksifosfini!]oksi}-2-(3-indolil)propiletiķskābes;

2-[[benzi!oksifosfinil]oksi]-2-(2-tienii)metiletiķskābes;

2-[[benziloksifosfinil]oksi]-2-(3-tienil)metiletiķskābes;

2-[[benziloksifosfinil]oksi]-2-(4-tienil)metiietiķskābes;

2-[[benziloksifosfinil]oksi]-2-(3-tienil)etiletiķskābes;

2-[[benziloksifosfinil]oksi]-2-(3-tienil)propiletiķskābes;

un farmaceitiski pieņemama sāls, hidrāta un vielu maisījuma.

38. Pielietojums saskaņā ar 36. punktu, kas atšķiras ar to, ka NAALADāzes inhibitoru izvēlas no grupas, kas sastāv no; 2-[(benziloksifosfinil)oksi]glutārskābes;

2-[(feniloksifosfinil)oksi]glutārskābes;

2-[[((oksi)fenilmetil)oksifosfinil]oksi]glutārskābes;

2-[(butiloksifosfinil)oksi]glutārskābes;

2-[[(3-metilbenzil)oksifosfinil]oksi]glutārskābes;

2-[(3-fenilpropiloksifosfinil)oksi]glutārskābes;

2-[[(4-fluorfenil)oksifosfinilļoksi]glutārskābes;

2-[(metiloksifosfinil)oksi]glutārskābes;

2-[(feniletiloksifosfinil)oksi]glutārskābes;

2-[[(4-metilbenzil)oksifosfinil]oksi]glutārskābes;

2-[[(4-fluorbenzil)oksifosfinil]oksi]glutārskābes;

2-[[(4-metoksibenzil)oksifosfinil]oksi]glutārskābes;

2-[(fosfono)oksi]glutārskābes;

2-[[(3-trifluormetilbenzil)oksifosfinil]oksi]glutārskābes;

2-[[(2-fluorbenzil)oksifosfinil]oksi]glutārskābes;

2-[[(pentafluorbenzil)oksifosfinil]oksi]glutārskābes;

un farmaceitiski pieņemama sāls, hidrāta vai vielu maisījuma.

39. Pielietojums saskaņā ar 32. punktu, kas atšķiras ar to, ka Rļ un R₂ ir alifātiskas grupas ar taisnu vai sazarotu virkni vai karbocikliskas grupas un X ir NR_rgrupa.

40. Pielietojums saskaņā ar 39. punktu, kas atšķiras ar to, ka šo inhibitoru izvēlas no grupas, kas sastāv no: 2-[[metiloksifosfinil]amino]glutārskābes;

2-[[etiloksifosfinil]amino]glutārskābes;

2-[[propiloksifosfinil]amino]glutārskābes;

2-[[butiloksifosfinil]amino]glutārskābes;

2-[[cikloheksiloksifosfinil]amino]glutārskābes;

2-[[(cikloheksil)metiloksifosfiniljamino]glutārskābes;

2-[[feniloksifosfinil]amino]glutārskābes;

2-[[benziloksifosfinil]amino]glutārskābes;

2-[[feniletiloksifosfinil]amino]glutārskābes;

2-[[fenilpropiloksifosfinil]amino]glutārskābes;

2-[[fenilbutiloksifosfinil]amino]glutārskābes;

2-[[(4-metilbenzil)oksifosfinil]amino]glutārskābes;

2-[[(4-fluorbenzil)oksifosfinil]amino]glutārskābes;

2-[[(2-fluorbenzil)oksifosfinil]amino]glutārskābes;

2-[[(pentafluorbenzil)oksifosfinil]amino]glutārskābes;

2-[[(metoksibenzil)oksifosfinil]amino]glutārskābes;

2-[[(2,3,4-trimetoksifenil)oksifosfinil]amino]glutārskābes;

2-[[(1 -naftil)oksifosfinil]amino]glutārskābes;

2-[[(2-naftil)oksifosfinil]amino]glutārskābes;

2-[[(1-naftil)metiloksifosfinil]amino]glutārskābes;

2-[[(2-naftil)metiloksifosfinil]amino]glutārskābes;

2-[[(1-naftil)etiloksifosfinil]amino]glutārskābes;

2-[[(2-naftil)etiloksifosfinil]amino]glutārskābes;

2-[[(1-naftil)propiloksifosfinil]amino]glutārskābes;

2-[[(2-naftil)propiloksifosfinil]amino]glutārskābes;

2-[[(1-naftii)butiloksifosfinil]amino]glutārskābes;

2-[[(2-naftil)butiloksifosfinil]amino]glutārskābes;

2-[[(fenilprop-2-enil)oksifosfinil]amino]glutārskābes;

2-[[benziloksifosfinil]amino]glutārskābes;

2-[[(2-fluorbenzil)oksifosfinil]amino]glutārskābes;

2-[[((oksi)fenilmetil)oksifosfinii]amino]glutārskābes;

2-[[(3-metilbenzil)oksifosfinil]amino]glutārskābes;

2-[[(4-fluorfenil)oksifosfinil]amino]glutārskābes;

2-[(fosfono)amino]glutārskābes;

2-[[(3-trifluormetilbenzil)oksifosfinil]amino]glutārskābes;

2-[[metiloksifosfinii]amino]-2-feniletiķskābes;

2-[[etiloksifosfinil]amino]-2-feniletiķskābes;

2-[[propiloksifosfinil]amino]-2-feniletiķskābes;

2-[[butiloksifosfinil]amino]-2-feniletiķskābes;

2-[[cikloheksiloksifosfinil]amino]-2-feniletiķskābes;

2-[[(cikloheksil)metiloksifosfinil]amino]-2-feniletiķskābes;

2-[[feniloksifosfinil]amino]-2-feniletiķskābes;

2-[[benziloksifosfinil]amino]-2-feniletiķskābes;

2-[[feniletiloksifosfinil]amino]-2-feniletiķskābes;

2-[[fenilpropiloksifosfinil]amino]-2-feniietiķskābes;

2-[[fenilbutiloksifosfinil]amino]-2-feniletiķskābes;

2-[[(2,3,4-trimetoksifenil)-3-oksifosfinil]amino]-2-feniletiķskābes;

2-[[(1-naftil)oksifosfinil]amino]-2-feniletiķskābes;

2-[[(2-naftil)oksifosfinil]amino]-2-feniletiķskābes;

3/

2-[[(1 -naftil)metiloksifosfinil]amino]-2-feniletiķskābes;

2-[[(2-naftil)metiloksifosfinil]amino]-2-feniletiķskābes;

2-[[(1 -naftil)etiloksifosfinil]amino]-2-feniletiķskābes;

2-[[(2-naftil)etiloksifosfinil]amino]-2-feniletiķskābes;

2-[[(1 -naftil)propiloksifosfinil]amino]-2-feniletiķskābes; 2-[[(2-naftil)propiloksifosfinil]amino]-2-feniletiķskābes;

2-[[(1 -naftil)butiloksifosfinil]amino]-2-feniletiķskābes;

2-[[(2-naftil)butiloksifosfinil]amino]-2-feniletiķskābes;

2-[[fenilprop-2-eniloksifosfinil]amino]-2-feniletiķskābes;

2-[[benziloksifosfinil]amino]-2-metiletiķskābes;

2-[[benziloksifosfinil]amino]-2-etiletiķskābes;

2-[[benziloksifosfinil]amino]-2-propiletiķskābes;

2-[[benziloksifosfinil]amino]-2-butiletiķskābes;

2-[[benziloksifosfinil]amino]-2-cikloheksiletiķskābes;

2-[[benziloksifosfinil]amino]-2-(cikloheksil)metiletiķskābes;

2-[[benziloksifosfinil]amino]-2-feniletiķskābes;

2-[[benziloksifosfinil]amino]-2-benziletiķskābes;

2-[[benziloksifosfinil]amino]-2-feniletiletiķskābes;

2-[[benziloksifosfinil]amino]-2-fenilpropiletiķskābes;

2-[[benziloksifosfinil]amino]-2-fenilbutiletiķskābes;

2-[[benziloksifosfinīl]amino]-2-(2,3,4-trimetoksifenil)etiķskābes;

2-[[benziloksifosfinil]amino]-2-(1-naftil)etiķskābes;

2-[[benziloksifosfinil]amino]-2-(2-naftil)etiķskābes;

2-[[benziloksifosfinil]amino]-2-(1-naftil)metiletiķskābes;

2-[[benziloksifosfinil]amino]-2-(2-naftil)metiletiķskābes;

2-[[benziloksifosfinil]amino]-2-(1-naftil)etiletiķskābes;

2-[[benziloksifosfinil]amino]-2-(2-naftil)etiletiķskābes;

2-[[benziloksifosfinil]amino]-2-(1-naftil)propiletiķskābes;

2-[[benziloksifosfinil]amino]-2-(2-naftil)propiletiķskābes;

2-[[benziloksifosfinil]amino]-2-(1-naftil)butiletiķskābes;

2-[[benziloksifosfinil]amino]-2-(2-naftil)butiletiķskābes;

2-[[benziloksifosfinil]amino]-2-fenilprop-2-eniletiķskābes;

2-[(metiloksifosfinil)amino]adipīnskābes;

2-[(benziloksifosfinil)amino]adipīnskābes;

2-[(metiloksifosfinil)amino]pimelīnskābes;

2-[(benziloksifosfinil)amino]pimelīnskābes;

2-[(metiloksifosfinil)amino]heksāndikarbonskābes;

2-[(benziloksifosfinil)amino]heksāndikarbonskābes;

2-[(metiloksifosfinil)amino]azelaīnskābes;

2-[(benziloksifosfinil)amino]azelaīnskābes;

2-[(metiloksifosfinil)amino]sebacīnskābes;

2-[(benziloksifosfinil)amino]sebacīnskābes;

2-[[(2-piridil)metiloksifosfinil]amino]glutārskābes;

2-[[(3-piridil)metiloksifosfinil]amino]glutārskābes;

2-[[(4-piridil)metiloksifosfinil]amino]glutārskābes;

2-[[(3-piridil)etiloksifosfinil]amino]glutārskābes;

2-[[(3-piridil)propiloksifosfinil]amino]glutārskābes;

2-[[(tetrahidrofuranil)metiloksifosfinil]amino]glutārskābes;

2-[[(tetrahidrofuranil)etiloksifosfinil]amino]glutārskābes;

2-[[(tetrahidrofuranil)propiloksifosfinil]amino]glutārskābes;

2-[[(2-indolil)metiloksifosfinil]amino]glutārskābes;

2-[[(3-indolil)metiloksifosfinil]amino]glutārskābes;

2-[[(4-indolil)metiloksifosfinil]aminoJglutārskābes;

2-[[(3-indolil)etiloksifosfinil]amino]glutārskābes;

2-[[(3-indolil)propiloksifosfinil]amino]glutārskābes;

2-[[(2-tienil)metiloksifosfinil]amino]glutārskābes;

2-[[(3-tienil)metiloksifosfinil]amino]glutārskābes;

2-[[(4-tienil)metiloksifosfinil]amino]glutārskābes;

2-[[(3-tienil)etiloksifosfinil]amino]glutārskābes;

2-[[(3-tienil)propiloksifosfinil]amino]glutārskābes;

2-[[(2-piridil)metiloksifosfinil]amino]-2-feniletiķskābes;

2-[[(3-piridil)metiloksifosfinil]amino]-2-feniletiķskābes;

2-[[(4-piridil)metiloksifosfinil]amino]-2-feniletiķskābes;

2-[[(3-piridil)etiloksifosfinil]amino]-2-feniletiķskābes;

2-[[(3-piridil)propiloksifosfinil]amino]-2-feniletiķskābes;

2-[[(tetrahidrofuranil)metiloksifosfinil]amino]-2-feniletiķskābes;

2-[[(tetrahidrofuranil)etiloksifosfinil]amino]-2-feniletiķskābes;

2-[[(tetrahidrofuranil)propiloksifosfinil]amino]-2-feniletiķskābes;

5 2-[[(2-indolil)metiloksifosfinil]amino]-2-feniletiķskābes; 2-[[(3-indolil)metiloksifosfinil]amino]-2-feniletiķskābes; 2-[[(4-indolil)metiloksifosfinil]amino]-2-feniletiķskābes; 2-[[(3-indolil)etiloksifosfinil]amino]-2-feniletiķskābes; 2-[[(3-indolil)propiloksifosfinil]amino]-2-feniletiķskābes;

10 2-[[(2-tienil)metiloksifosfinil]amino]-2-feniletiķskābes; 2-[[(3-tienil)metiloksifosfinil]amino]-2-feniletiķskābes; 2-[[(4-tienil)metiloksifosfinil]amino]-2-feniletiķskābes; 2-[[(3-tienil)etiloksifosfinil]amino]-2-feniletiķskābes; 2-[[(3-tienil)propiloksifosfinil]amino]-2-feniletiķskābes;

15 2-[[benziloksifosfinil]amino]-2-(2-piridil)metiletiķskābes; 2-[[benziloksifosfinil]amino]-2-(3-piridil)metiletiķskābes; 2-[[benziloksifosfinil]amino]-2-(4-piridil)metiletiķskābes; 2-[[benziloksifosfinil]amino]-2-(3-piridil)etiletiķskābes; 2-[[benziloksifosfinil]amino]-2-(3-piridil)propiletiķskābes;

20 2-[[benziloksifosfinil]amino]-2-(tetrahidrofuranil)metiletiķskābes; 2-[[benziloksifosfinil]amino]-2-(tetrahidrofuranil)etiletiķskābes; 2-[[benziloksifosfinil]amino]-2-(tetrahidrofuranil)propiletiķskābes; 2-[[benziloksifosfinil]amino]-2-(2-indolil)metiletiķskābes; 2-[[benziloksifosfinil]amino]-2-(3-indolil)metiletiķskābes;

25 2-[[benziloksifosfinil]amino]-2-(4-indolil)metiletiķskābes; 2-[[benziloksifosfinil]amino]-2-(3-indolil)etiletiķskābes; 2-[[benziloksifosfinil]amino]-2-(3-indolil)propiletiķskābes; 2-[[benziloksifosfinil]amino]-2-(2-tienil)metiletiķskābes; 2-[[benziloksifosfinil]amino]-2-(3-tienil)metiletiķskābes;

30 2-[[benziloksifosfinil]amino]-2-(4-tienil)metiletiķskābes; 2-[[benziloksifosfinil]amino]-2-(3-tienil)etiletiķskābes; 2-[[benziloksifosfinil]amino]-2-(3-tienil)propiletiķskābes;

un farmaceitiski pieņemama sāls, hidrāta un vielu maisījuma.

41. Pielietojums saskaņā ar 39. punktu, kas atšķiras ar to, ka NAALADāzes inhibitoru izvēlas no grupas, kas sastāv no: 2-[(benziloksifosfinil)amino]glutārskābes;

2-[(feniloksifosfinil)amino]glutārskābes;

2-[[((oksi)fenilmetil)oksifosfinil]amino]glutārskābes;

2-[(butiloksifosfinil)amino]glutārskābes;

2-[[(3-metilbenzil)oksifosfinil]amino]glutārskābes;

2-[(3-fenilpropiloksifosfinil)amino]glutārskābes;

2-[[(4-fluorfenii)oksifosfinil]amino]glutārskābes;

2-[(metiloksifosfinil)amino]glutārskābes;

2-[(feniletiloksifosfinil)amino]glutārskābes;

2-[[(4-metilbenzil)oksifosfinil]amino]glutārskābes;

2-[[(4-fiuorbenzil)oksifosfinil)amino]glutārskābes;

2-[[(4-metoksibenzil)oksifosfinil]amino]glutārskābes;

2-[(fosfono)amino]glutārskābes;

2-[[(3-trifluormetilbenzil)oksifosfinil]amino]glutārskābes;

2-[[(2-fluorbenzil)oksifosfinil]amino]glutārskābes;

2-[[(pentafluorbenzil)oksifosfinil]amino]glutārskābes;

un farmaceitiski pieņemama sāls, hidrāta vai vielu maisījuma.

42. Pielietojums saskaņā ar 32. punktu, kas atšķiras ar to, ka Rļ vai R₂ ir heterocikliska grupa un X ir CH₂-grupa.

43. Pielietojums saskaņā ar 42. punktu, kas atšķiras ar to, ka NAALADāzes inhibitoru izvēlas no grupas, kas sastāv no: 2-[[(2-piridil)oksifosfinil]metil]glutārskābes;

2-[[(3-piridil)oksifosfinil]metil]glutārskābes;

2-[[(4-piridil)oksifosfinil]metil]glutārskābes;

2-[[(tetrahidrofuranil)oksifosfinil]metil]giutārskābes;

2-[[(2-indolil)oksifosfinil]metil]glutārskābes;

2-[[(3-indolil)oksifosfinil]metiI]glutārskābes;

2-[[(4-indoIil)oksifosfinil]metil]glutārskābes;

2-[[(2-tienil)oksifosfinil]metil]glutārskābes;

2-[[(3-tienil)oksifosfinil]metil]glutārskābes;

2- [[(4-tienil)oksifosfinil]metil]glutārskābes;

3- [(2-piridil)oksifosfinil]-2-fenilpropionskābes;

3-[(3-piridil)oksifosfinil]-2-fenilpropionskābes;

3-[(4-piridil)oksifosfinil]-2-fenilpropionskābes;

3-[(tetrahidrofuranil)oksifosfinil]-2-fenilpropionskābes;

3-[(2-indolil)oksifosfiniI]-2-fenilpropionskābes;

3-[(3-indolil)oksifosfinil]-2-fenilpropionskābes;

3-[(4-indolil)oksifosfinil]-2-fenilpropionskābes;

3-[(2-tienil)oksifosfinil]-2-fenilpropionskābes;

3-[(3-tienil)oksifosfinil]-2-fenilpropionskābes;

3-[(4-tienil)oksifosfinil]-2-fenilpropionskābes;

3-(benziloksifosfinil)-2-(2-piridil)propionskābes;

3-(benziloksifosfinil)-2-(3-piridil)propionskābes;

3-(benziloksifosfinil)-2-(4-piridil)propionskābes;

3-(benziloksifosfinil)-2-(tetrahidrofuranil)propionskābes;

3-(benziloksifosfinil)-2-(2-indolil)propionskābes;

3-(benziloksifosfinil)-2-(3-indolil)propionskābes;

3-(benziloksifosfinil)-2-(4-indolil)propionskābes;

3-(benziloksifosfinil)-2-(2-tienil)propionskābes;

3-(benziloksifosfinil)-2-(3-tienil)propionskābes;

3-(benziloksifosfinil)-2-(4-tienil)propionskābes;

un farmaceitiski pieņemama sāls, hidrāta vai vielu maisījuma.

44. Pielietojums saskaņā ar 32. punktu, kas atšķiras ar to, ka Fķ vai R₂ ir heterocikliska grupa un X ir skābekļa atoms.

45. Pielietojums saskaņā ar 44. punktu, kas atšķiras ar to, ka NAALADāzes inhibitoru izvēlas no grupas, kas sastāv no: 2-[[(2-piridil)oksifosfinil]oksi]glutārskābes;

2-[[(3-piridil)oksifosfinil]oksi]glutārskābes;

2-[[(4-piridil)oksifosfinii]oksi]glutārskābes;

2-[[(tetrahidrofuranil)oksifosfinil]oksi]glutārskābes;

2-[[(2-indolil)oksifosfinil]oksi]glutārskābes;

2-[[(3-indolil)oksifosfiniljoksi]glutārskābes;

2-[[(4-indolil)oksifosfinil]oksi]glutārskābes;

2-[[(2-tienil)oksifosfinil]oksi]glutārskābes;

2-[[(3-tienil)oksifosfinil]oksi]glutārskābes;

2-[[(4-tienil)oksifosfinil]oksi]glutārskābes;

2-[[(2-piridil)oksifosfinil]oksi]-2-feniletiķskābes;

2-[[(3-piridil)oksifosfinil]oksi]-2-feniletiķskābes;

2-[[(4-piridil)oksifosfinil]oksi]-2-feniletiķskābes;

2-[[(tetrahidrofuranil)oksifosfinil]oksi]-2-feniletiķskābes;

2-[[(2-indolil)oksifosfinil]oksi]-2-feniletiķskābes;

2-[[(3-indolil)oksifosfinil]oksi]-2-feniletiķskābes;

2-[[(4-indolil)oksifosfinil]oksi]-2-feniletiķskābes;

2-[[(2-tienil)oksifosfinil]oksi]-2-feniletiķskābes;

2-[[(3-tienil)oksifosfinil]oksi]-2-feniletiķskābes;

2-[[(4-tienil)oksifosfinil]oksi]-2-feniletiķskābes;

2-[[benziloksifosfinil]oksi]-2-(2-piridil)etiķskābes;

2-[[benziloksifosfinil]oksi]-2-(3-piridil)etiķskābes;

2-[[benziloksifosfinil]oksi]-2-(4-piridil)etiķskābes;

2-[[benziloksifosfinil]oksi]-2-(tetrahidrofuranil)etiķskābes;

2-[[benziloksifosfinil]oksi]-2-(2-indolil)etiķskābes;

2-[[benziloksifosfinil]oksi]-2-(3-indolil)etiķskābes;

2-[[benziloksifosfinil]oksij-2-(4-indolil)etiķskābes;

2-[[benziloksifosfinil]oksi]-2-(2-tienil)etiķskābes;

2-[[benziloksifosfinil]oksi]-2-(3-tienil)etiķskābes;

2-[[benziloksifosfinil]oksi]-2-(4-tienil)etiķskābes;

un farmaceitiski pieņemama sāls, hidrāta vai vielu maisījuma.

46. Pielietojums saskaņā ar 32. punktu, kas atšķiras ar to, ka R, vai R₂ ir heterocikliska grupa un X ir NR^grupa.

47. Pielietojums saskaņā ar 46. punktu, kas atšķiras ar to, ka NAALADāzes inhibitoru izvēlas no grupas, kas sastāv no: 2-[[(2-piridil)oksifosfinil]amino]glutārskābes;

2-[[(3-piridil)oksifosfinil]amino]glutārskābes;

2-[[(4-piridil)oksifosfinil]amino]glutārskābes;

2-[[(tetrahidrofuranil)oksifosfinil]amino]glutārskābes;

2-[[(2-indolil)oksifosfinil]amino]glutārskābes;

2-[[(3-indolil)oksifosfinil]amino]glutārskābes;

5 2-[[(4-indolil)oksifosfinil]amino]glutārskābes; 2-[[(2-tienil)oksifosfinil]amino]glutārskābes; 2-[[(3-tienil)oksifosfinil]amino]glutārskābes; 2-[[(4-tienil)oksifosfinil]amino]glutārskābes; 2-[[(2-piridil)oksifosfinil]amino]-2-feniletiķskābes;

10 2-[[(3-p i rid il) oks if osf i n i I] amino]-2-f en iletiķskābes;

2-[[(4-piridil)oksifosfinil]amino]-2-feniletiķskābes; 2-[[(tetrahidrofuranil)oksifosfinil]amino]-2-feniletiķskābes; 2-[[(2-indolil)oksifosfinil]amino]-2-feniletiķskābes; 2-[[(3-indolil)oksifosfinil]amino]-2-feniletiķskābes;

15 2-[[(4-i n dolil)oksif osf in i l]amino]-2-f en ileti ķskābes;

2-[[(2-tienil)oksifosfinil]amino]-2-feniletiķskābes; 2-[[(3-tienil)oksifosfinil]amino]-2-feniletiķskābes; 2-[[(4-tienil)oksifosfinil]amino]-2-feniletiķskābes; 2-[[benziloksifosfinil]amino]-2-(2-piridil)etiķskābes;

20 2-[[benziloksifosfinil]amino]-2-(3-piridil)etiķskābes; 2-[[benziloksifosfinil]amino]-2-(4-piridil)etiķskābes; 2-[[benziloksifosfinil]amino]-2-(tetrahidrofuranil)etiķskābes; 2-[[benziloksifosfinil]amino]-2-(2-indolil)etiķskābes; 2-[[benziloksifosfinil]amino]-2-(3-indolil)etiķskābes;

25 2-[[benziloksifosfinil]amino]-2-(4-indolil)etiķskābes; 2-[[benziloksifosfiniljamino]-2-(2-tienil)etiķskābes; 2-[[benziloksifosfinil]amino]-2-(3-tienil)etiķskābes; 2-[[benziloksifosfinil]amino]-2-(4-tienil)etiķskābes; un farmaceitiski pieņemama sāls, hidrāta vai vielu maisījuma.

30

48. NAALADāzes inhibitora pielietojums NAALADāzes fermenta aktivitātes inhibēšanai dzīvniekiem, kuri cieš no traucējuma, saistīta ar NAALADāzes fermenta aktivitātes palielināšanu.

49. Pielietojums saskaņā ar 48. punktu, kas atšķiras ar to, ka NAALADāzes inhibitoru izvēlas no grupas, kas sastāv no: glutamāta atvasinājuma oksifosfinilatvasinājuma; skābā peptīda analoga; konformācijas ziņā traucētas glutamāta imitētājvielas; un šo vielu maisījumiem.

50. Pielietojums saskaņā ar 49. punktu, kas atšķiras ar to, ka NAALADāzes inhibitors ir glutamāta atvasinājuma oksifosfinilatvasinājums.

51. Pielietojums saskaņā ar 48. punktu, kas atšķiras ar to, ka NAALADāzes inhibitoru lieto kopā ar papildu terapeitisku līdzekli, kuru izvēlas no grupas, kas sastāv no: terapeitiskiem hormoniem, ķimioterapeitiskiem hormoniem, anti-angioģenēzes līdzekļiem, ar radioaktīvo izotopu iezīmētiem savienojumiem un šo vielu maisījumiem.

52. Pielietojums saskaņā ar 48. punktu, kas atšķiras ar to, ka traucējums, kas saistīts ar NAALADāzes aktivitātes izmaiņu, ir prostatas slimība un šo prostatas slimību izvēlas no grupas, kas sastāv no prostatas vēža un labdabīgas prostatas hiperplāzijas.

53. Pielietojums saskaņā ar 48. punktu, kas atšķiras ar to, ka NAALADāzes inhibitorā ietilpst savienojums ar sekojošu formulu:

O

Ri -p

OH

R2

X ^COOH

Formula I, kur

R, ir ūdeņraža atoms, C, - C₉ alkilgrupa ar taisnu vai sazarotu virkni, C₂ - C₉ alkenilgrupa ar taisnu vai sazarotu virkni, C₃ - C₈ cikloalkil-, C₅ - C₇ cikloalkenil- vai Ar_r grupa;

X ir CH₂-grupa, skābekļa atoms vai NRļ-grupa, kur R., ir definēts iepriekš; un

R₂ ir C, - C₉ alkiigrupa ar taisnu vai sazarotu virkni, C₂ - C₉alkenilgrupa ar taisnu vai sazarotu virkni, C₃ - C₈cikloalkil-, C₅ - C₇ cikloalkenil- vai Ar,- grupa; šī alkil-, alkenil-, cikloalkil-, cikloalkenil- vai arilgrupa var būt aizvietota ar karbonskābi;

minētās alkil-, alkenil-, cikloalkil-, cikloalkenil- vai arilgrupas var būt aizvietotas ar C₃ - C₈ cikloalkil-, C₃ vai C₅ cikloalkil-, C₅ - C₇ cikloalkenil-, C, - C₄ alkil-, C, - C₄ alkenilgrupām, halogēna atomu, oksi-, karboksi- nitro,trifluormetilgrupām, C, - C₆ alkil- vai C, - C₆ alkenilgrupu ar taisnu vai sazarotu virkni, C, - C₄ alkoksi-, C, - C₄ alkeniloksi-, fenoksi-, benziloksi-, amino- vai Ar,-grupu un kur Ar,-grupu izvēlas no grupas, kura sastāv no

1- naftil-, 2-naftil-, 2-indolil-, 3-indolil-, 4-indolil-, 2-furil-, 3-furil-, tetrahidrofuranil-, 2-tienil-, 3-tienil-, 4-tienil-, 2-, 3-, vai 4-piridil- vai fenilgrupas, kas satur no viena līdz pieciem aizvietotājiem, kurus neatkarīgi izvēlas no grupas, kas sastāv no ūdeņraža atoma, halogēna atoma, oksi-, karboksi-, nitro-, trifluormetil-, C, - C₆ alkil- vai C, - C₆ alkenilgrupas ar taisnu vai sazarotu virkni, C, - C₄ alkoksi- vai C, - C₄ alkeniloksi-, fenoksi-, benziloksi- un aminogrupām; vai šī savienojuma farmaceitiski pieņemami sāļi, hidrāti vai vielu maisījumi.

54. Pielietojums saskaņā ar 53. punktu, kas atšķiras ar to, ka R, un R₂ ir alifātiskas grupas ar taisnu vai sazarotu virkni vai karbocikliskas grupas un X ir CH₂-grupa.

55. Pielietojums saskaņā ar 54. punktu, kas atšķiras ar to, ka NAALADāzes inhibitoru izvēlas no grupas, kas sastāv no:

2- [[metiloksifosfinil]metil]glutārskābes;

2-[[etiloksifosfinil]metil]glutārskābes;

2-[[propiloksifosfinii]metil]glutārskābes;

2-[[butiloksifosfinil]metil]glutārskābes;

2-[[cikloheksiloksifosfinil]meti!]glutārskābes;

2-[[(cikloheksil)metiloksifosfinil]metil]glutārskābes;

2-[[feniloksifosfinii]metii]glutārskābes;

2-[[benziloksifosfinil]metil]glutārskābes;

2-[[feniletiloksifosfinil]metil]glutārskābes;

2-[[fenilpropiloksifosfinil]metil]glutārskābes;

2-[[fenilbutiloksifosfinil]metil]glutārskābes;

2-[[(4-metilbenzil)oksifosfinil]metil]glutārskābes;

2-[[(4-fluorbenzil)oksifosfinil]metil]glutārskābes;

2-[[(2-fluorbenzil)oksifosfinil]metil]glutārskābes;

2-[[(pentafluorbenzil)oksifosfinil]metil]glutārskābes;

2-[[(metoksibenzil)oksifosfinil]metil]glutārskābes;

2-[[(2,3,4-trimetoksifenil)oksifosfinil]metil]glutārskābes;

2-[[(1-naftil)oksifosfinil]metil]glutārskābes;

2-[[(2-naftil)oksifosfinil]metil]glutārskābes;

2-[[(1-naftil)metiloksifosfinil]metil]glutārskābes;

2-[[(2-naftil)metiloksifosfinil]metil]glutārskābes;

2-[[(1 -naftil)butiloksifosfinil]metil]glutārskābes;

2-[[(2-naftil)butiloksifosfinil]metil]glutārskābes;

2-[[(fenilprop-2-enil)oksifosfinil]metil]glutārskābes;

2-[[(2-fluorbenzil)oksifosfinil]metil]glutārskābes;

2-[[(4-fluorfenil)oksifosfinil]metil]glutārskābes;

2-[[((oksi)fenilmetil)oksifosfinil]metil]glutārskābes;

2-[[(3-metilbenzil)oksifosfinil]metil]glutārskābes;

2-(fosfonometil)glutārskābes;

2- [[(3-trifluormetilbenzil)oksifosfinil]metil]glutārskābes;

3- (metiloksifosfinil)-2-fenilpropionskābes;

3-(etiloksifosfinil)-2-fenilpropionskābes;

3-(propiloksifosfinil)-2-fenilpropionskābes;

3-(butiloksifosfinil)-2-fenilpropionskābes;

3-(cikloheksiloksifosfinil)-2-fenilpropionskābes;

3-((cikIoheksil)metiloksifosfinil)-2-fenilpropionskābes;

3-(feniloksifosfinil)-2-fenilpropionskābes;

3-(benziloksifosfinil)-2-fenilpropionskābes;

3-(feniletiloksifosfinil)-2-fenilpropionskābes;

3-(fenilpropiloksifosfinil)-2-fenilpropionskābes;

5 3-(fenilbutiloksifosfinil)-2-fenilpropionskābes;

3-((2,3,4-trimetoksifenil)-3-oksifosfinil)-2-fenilpropionskābes; 3-((1-naftil)oksifosfinil)-2-fenilpropionskābes;

3-((2-naftil)oksifosfinil)-2-fenilpropionskābes;

3-((1-naftil)metiloksifosfinil)-2-fenilpropionskābes;

1 o 3-((2-naftil)metiloksifosfinil)-2-fenilpropionskābes;

3-((1 -naftil)etiloksifosfinil)-2-fenilpropionskābes; 3-((2-naftil)etiloksifosfinil)-2-fenilpropionskābes;

3-((1 -naftil)propiloksifosfinil)-2-fenilpropionskābes; 3-((2-naftil)propiloksifosfinil)-2-fenilpropionskābes;

15 3-((1 -n aft i I )b uti loks if osf inil)-2-fenilpropionskābes;

3-((2-naftil)butiloksifosfinil)-2-fenilpropionskābes; 3-(fenilprop-2-eniloksifosfinil)-2-fenilpropionskābes; 2-[(benziloksifosfinil)metil]glutārskābes; 2-[(metiioksifosfinil)metil]adipīnskābes;

20 2-[(benziloksifosfinil)metil]adipīnskābes; 2-[(metiloksifosfinil)metil]pimelīnskābes; 2-[(benziloksifosfinil)metil]pimelīnskābes; 2-[(metiloksifosfinil)metil]heksāndikarbonskābes; 2-[(benziloksifosfinil)metil]heksāndikarbonskābes;

25 2-[(metiloksifosfinil)metil]azelaīnskābes; 2-[(benziloksifosfinil)metil]azelaīnskābes; 2-[(metiloksifosfinil)metil]sebacīnskābes;

2- [(benziloksifosfinil)metil]sebacīnskābes;

3- (benziloksifosfinil)-2-metilpropionskābes;

30 3-(benziloksifosfinil)-2-etilpropionskābes;

3-(benziIoksifosfinil)-2-propilpropionskābes;

3-(benziloksifosfinil)-2-butilpropionskābes;

3-(benziloksifosfinil)-2-cikloheksilpropionskābes;

3-(benziloksifosfinil)-2-(cikloheksil)metilpropionskābes;

3-(benziloksifosfinil)-2-fenilpropionskābes;

3-(benziloksifosfinil)-2-benzilpropionskābes;

5 3-(benziloksifosfinil)-2-feniletilpropionskābes; 3-(benziloksifosfinil)-2-fenilpropilpropionskābes; 3-(benziloksifosfinil)-2-fenilbutilpropionskābes; 3-(benziloksifosfinil)-2-(2,3,4-trimetoksifenil)propionskābes 3-(benziloksifosfinil)-2-(1-naftil)propionskābes;

10 3-(benziloksifosfinil)-2-(2-naftil)propionskābes; 3-(benziloksifosfinil)-2-(1-naftil)metilpropionskābes; 3-(benziloksifosfinil)-2-(2-naftil)metilpropionskābes; 3-(benziloksifosfinil)-2-(1-naftil)etilpropionskābes; 3-(benziloksifosfinil)-2-(2-naftii)etilpropionskābes;

15 3-(benziloksifosfinil)-2-(1 -naftil)propilpropionskābes; 3-(benziloksifosfinil)-2-(2-naftil)propilpropionskābes; 3-(benziloksifosfinil)-2-(1-naftil)butilpropionskābes; 3-(benziloksifosfinil)-2-(2-naftil)butilpropionskābes; 3-(benziloksifosfinil)-2-fenilprop-2-enilpropionskābes;

20 2-[[(2-piridil)metiloksifosfinil]metil]glutārskābes; 2-[[(3-piridil)metiloksifosfinil]metil]glutārskābes; 2-[[(4-piridil)metiloksifosfinil]metil]glutārskābes; 2-[[(3-piridil)etiloksifosfinil]metil]glutārskābes; 2-[[(3-piridil)propiloksifosfinil]metil]glutārskābes;

25 2-[[(tetrahidrofuranil)metiloksifosfinil]metil]glutārskābes; 2-[[(tetrahidrofuranil)etiloksifosfinil]metil]glutārskābes; 2-[[(tetrahidrofuranil)propiloksifosfinil]metil]glutārskābes; 2-[[(2-indolil)metiloksifosfinil]metil]glutārskābes; 2-[[(3-indolil)metiloksifosfinil]metil]glutārskābes;

30 2-[[(4-indolil)metiloksifosfinil]metil]glutārskābes; 2-[[(3-indolil)etiloksifosfinil]metil]glutārskābes; 2-[[(3-indolil)propiloksifosfinil]metil]glutārskābes;

2-[[(2-tienil)metiloksifosfinil]metil]glutārskābes;

2-[[(3-tienil)metiloksifosfinil]metil]glutārskābes;

2-[[(4-tienil)metiloksifosfinil]metil]glutārskābes;

2-[[(3-tienil)etiloksifosfinil]metil]glutārskābes;

2- [[(3-tienil)propiloksifosfinil]metil]glutārskābes;

3- [(2-piridil)metiloksifosfinil]-2-fenilpropionskābes; 3-[(3-piridil)metiloksifosfinil]-2-fenilpropionskābes; 3-[(4-piridil)metiloksifosfinil]-2-fenilpropionskābes; 3-[(3-piridil)etiloksifosfinil]-2-fenilpropionskābes; 3-[(3-piridil)propiloksifosfinil]-2-fenilpropionskābes; 3-[(tetrahidrofuranil)metiloksifosfinil]-2-fenilpropionskābes; 3-[(tetrahidrofuranil)etiloksifosfinil]-2-fenilpropionskābes; 3-[(tetrahidrofuranil)propiloksifosfinil]-2-fenilpropionskābes; 3-[(2-indolil)metiloksifosfinil]-2-fenilpropionskābes; 3-[(3-indolil)metiloksifosfinil]-2-fenilpropionskābes; 3-[(4-indolil)metiloksifosfinil]-2-fenilpropionskābes; 3-[(3-indolil)etiloksifosfinil]-2-fenilpropionskābes; 3-[(3-indolil)propiloksifosfinil]-2-fenilpropionskābes; 3-[(2-tienil)metiloksifosfinil]-2-fenilpropionskābes; 3-[(3-tienil)metiloksifosfinil]-2-fenilpropionskābes; 3-[(4-tienil)metiloksifosfinil]-2-fenilpropionskābes; 3-[(3-tienil)etiloksifosfinil]-2-fenilpropionskābes; 3-[(3-tienil)propiloksifosfinil]-2-fenilpropionskābes; 3-(benziloksifosfinil)-2-(2-piridil)metilpropionskābes; 3-(benziloksifosfinil)-2-(3-piridil)metilpropionskābes; 3-(benziloksifosfinil)-2-(4-piridil)metilpropionskābes; 3-(benziloksifosfinil)-2-(3-piridil)etilpropionskābes; 3-(benziloksifosfinil)-2-(3-piridil)propilpropionskābes; 3-(benziloksifosfinil)-2-(tetrahidrofuranil)metilpropionskābes; 3-(benziloksifosfinil)-2-(tetrahidrofuranil)etilpropionskābes; 3-(benziloksifosfinil)-2-(tetrahidrofuranil)propilpropionskābes; 3-(benziloksifosfinil)-2-(2-indolil)metilpropionskābes;

3-(benziloksifosfinil)-2-(3-indolil)metilpropionskābes;

3-(benziloksifosfinil)-2-(4-indolil)metilpropionskābes;

3-(benziloksifosfinil)-2-(3-indolil)etilpropionskābes;

3-(benziloksifosfinil)-2-(3-indolil)propilpropionskābes;

3-(benziloksifosfinil)-2-(2-tienii)metilpropionskābes;

3-(benziloksifosfinil)-2-(3-tienil)metilpropionskābes;

3-(benziloksifosfinil)-2-(4-tienil)metilpropionskābes;

3-(benziloksifosfinil)-2-(3-tienil)etilpropionskābes;

3-(benziloksifosfinil)-2-(3-tienil)propilpropionskābes;

un farmaceitiski pieņemama sāls, hidrāta vai vielu maisījuma.

56. Pielietojums saskaņā ar 54. punktu, kas atšķiras ar to, ka NAALADāzes inhibitoru izvēlas no grupas, kas sastāv no: 2-[(benziloksifosfinil)metil]glutārskābes;

2-[(feniloksifosfinil)metil]glutārskābes;

2-[[((oksi)fenilmetil)oksifosfinil]metil]glutārskābes;

2-[(butiioksifosfinil)metil]glutārskābes;

2-[[(3-metilbenzil)oksifosfinil]metil]glutārskābes;

2-[(3-fenilpropiloksifosfinil)metil]glutārskābes;

2-[[(4-fluorfenil)oksifosfinil]metil]glutārskābes;

2-[(metiloksifosfinil)metil]glutārskābes;

2-[(feniletiloksifosfinil)metil]glutārskābes;

2-[[(4-metilbenzil)oksifosfinil]metil]glutārskābes;

2-[[(4-fluorbenzil)oksifosfinil]metil]glutārskābes;

2-[[(4-metoksibenzil)oksifosfinil]metil]glutārskābes;

2-(fosfonometil)glutārskābes;

2-[[(3-trifluormetilbenzil)oksifosfinil]metil]glutārskābes;

2-[[(2-fluorbenzil)oksifosfinil]metil]glutārskābes;

2-[[(pentafluorbenzil)oksifosfinil]metil]glutārskābes;

un farmaceitiski pieņemama sāls, hidrāta vai vielu maisījuma.

57. Pielietojums saskaņā ar 53. punktu, kas atšķiras ar to, ka R, un R₂ ir alifātiskas grupas ar taisnu vai sazarotu virkni vai karbocikliskas grupas un X ir skābekļa atoms.

58. Pielietojums saskaņā ar 57. punktu, kas atšķiras ar to, ka NAALADāzes inhibitoru izvēlas no grupas, kas sastāv no: 2-[[metiloksifosfinil]oksi]glutārskābes;

2-[[etiloksifosfinil]oksi]glutārskābes;

2-[[propiloksifosfinil]oksi]glutārskābes;

2-[[butiloksifosfinil]oksi]glutārskābes;

2-[[cikloheksiloksifosfinil]oksi]glutārskābes;

2-[[(cikloheksil)metiloksifosfinil]oksi]glutārskābes;

2-[[feniloksifosfinil]oksi]glutārskābes;

2-[[benziloksifosfinil]oksi]glutārskābes;

2-[[feniletiloksifosfinil]oksi]glutārskābes;

2-[[fenilpropiloksifosfinil]oksi]glutārskābes;

2-[[fenilbutiloksifosfinil]oksi]glutārskābes;

2-[[(4-metilbenzil)oksifosfinil]oksi]glutārskābes;

2-[[(4-fluorbenzil)oksifosfinil]oksi]glutārskābes;

2-[[(2-fluorbenzil)oksifosfinil]oksi]glutārskābes;

2-[[(pentafluorbenzil)oksifosfinil]oksi]glutārskābes;

2-[[(metoksibenzil)oksifosfinil]oksi]glutārskābes;

2-[[(2,3,4-trimetoksifenil)oksifosfinil]oksi]glutārskābes;

2-[[(1 -naftil)oksifosfinil]oksi]glutārskābes;

2-[[(2-naftil)oksifosfinil]oksi]glutārskābes;

2-[[(1 -naftil)metiloksifosfinil]oksi]glutārskābes;

2-[[(2-naftil)metiloksifosfinil]oksi]glutārskābes;

2-[[(1 -naftil)etiloksifosfinil]oksi]glutārskābes;

2-[[(2-naftil)etiloksifosfinil]oksi]glutārskābes;

2-[[(1-naftil)propiloksifosfinilJoksi]glutārskābes;

2-[[(2-naftil)propiloksifosfinil]oksi]glutārskābes;

2-[[(1 -naftil)butiloksifosfinii]oksi]glutārskābes;

2-[[(2-naftil)butiloksifosfinil]oksi]glutārskābes;

2-[[(fenilprop-2-enil)oksifosfinil]oksi]glutārskābes;

2-[[benziloksifosfinil]oksi]glutārskābes;

2-[[(4-fluorfenil)oksifosfinil]oksi]glutārskābes;

2-[[((oksi)fenilmetil)oksifosfinil]oksi]glutārskābes;

2-[[(3-metilbenzil)oksifosfinil]oksi]glutārskābes;

2-[(fosfono)oksi]glutārskābes;

2-[[(3-trifluormetilbenzil)oksifosfinil]oksi]glutārskābes;

2-[[metiloksifosfinil]oksi]-2-feniletiķskābes;

2-[[etiloksifosfinil]oksi]-2-feniletiķskābes;

2-[[propiloksifosfinil]oksi]-2-feniletiķskābes;

2-[[butiloksifosfinil]oksi]-2-feniletiķskābes;

2-[[cikloheksiloksifosfinil]oksi]-2-feniletiķskābes;

2-[[(cikloheksil)metiloksifosfinil]oksi]-2-feniletiķskābes;

2-[[feniloksifosfinil]oksi]-2-feniletiķskābes;

2-[[benziloksifosfinil]oksi]-2-feniletiķskābes;

2-[[feniletiloksifosfinil]oksi]-2-feniletiķskābes;

2-[[fenilpropiloksifosfinil]oksil]-2-feniletiķskābes;

2-[[fenilbutiloksifosfinil]oksi]-2-feniletiķskābes;

2-[[(2,3,4-trimetoksifenil)-3-oksifosfinil]oksi]-2-feniletiķskābes;

2-[[(2-naftil)oksifosfinil]oksi]-2-feniletiķskābes;

2-[[(3-naftil)oksifosfinil]oksi]-2-feniletiķskābes;

2-[[(4-naftil)oksifosfinil]oksi]-2-feniletiķskābes;

2-[[(2-naftil)metiloksifosfinil]oksi]-2-feniletiķskābes;

2-[[(3-naftil)metiloksifosfinil]oksi]-2-feniletiķskābes;

2-[[(4-naftil)metiloksifosfinil]oksi]-2-feniletiķskābes;

2-[[(3-naftil)etiloksifosfinil]oksi]-2-feniletiķskābes;

2-[[(3-naftil)propiloksifosfinil]oksi]-2-feniletiķskābes;

2-[[(3-naftil)butiloksifosfinil]oksi]-2-feniletiķskābes;

2-[[fenilprop-2-eniloksifosfinil]oksi]-2-feniletiķskābes;

2-[(metiloksifosfinil)oksi]adipīnskābes;

2-[(benziloksifosfinil)oksi]adipīnskābes;

2-[(metiloksifosfinil)oksi]pimelīnskābes;

2-[(benziloksifosfinil)oksi]pimelīnskābes;

2-[(metiloksifosfinil)oksi]heksāndikarbonskābes;

2-[(benziloksifosfinil)oksi]heksāndikarbonskābes;

2-[(metiloksifosfinil)oksi]azelaīnskābes;

2-[(bēnziloksifosfinil)oksi]azelaīnskābes;

2-[(metiloksifosfinil)oksi]sebacīnskābes;

2-[(benziloksifosfinil)oksi]sebacīnskābes;

5 2-[[benziloksifosfinil]oksi]-2-metiletiķskābes; 2-[[benziioksifosfinil]oksi]-2-etiletiķskābes; 2-[[benziloksifosfinil]oksi]-2-propiletiķskābes; 2-[[benziloksifosfinil]oksi]-2-butiletiķskābes; 2-[[benziloksifosfinil]oksi]-2-cikloheksiletiķskābes;

10 2-[[benziloksifosfinil]oksi]-2-(cikloheksil)metiletiķskābes; 2-[[benziloksifosfinil]oksi]-2-feniletiķskābes; 2-[[benziloksifosfinii]oksi]-2-benziletiķskābes; 2-[[benziloksifosfinil]oksi]-2-feniletiletiķskābes; 2-[[benziloksifosfinil]oksi]-2-fenilpropiletiķskābes;

15 2-[[benziloksifosfinii]oksi]-2-fenilbutiletiķskābes;

2-[[benziloksifosfinil]oksi]-2-(2,3,4-trimetoksifenil)etiķskābes; 2-[[benziloksifosfinil]oksi]-2-(1-naftil)etiķskābes; 2-[[benziloksifosfinil]oksi]-2-(2-naftil)etiķskābes; 2-[[benziloksifosfinii]oksi]-2-(1 -naftil)metiletiķskābes;

20 2-[[benziloksifosfinil]oksi]-2-(2-naftil)metiletiķskābes; 2-[[benziloksifosfinil]oksi]-2-(1 -naftil)etiletiķskābes; 2-[[benziloksifosfinil]oksi]-2-(2-naftil)etiletiķskābes; 2-[[benziloksifosfinil]oksi]-2-(1 -naftil)propiletiķskābes; 2-[[benziloksifosfinil]oksi]-2-(2-naftil)propiletiķskābes;

25 2-[[benziloksifosf inil]oksi]-2-(1 -naftil)butiletiķskābes; 2-[[benziloksifosfinil]oksi]-2-(2-naftil)butiletiķskābes; 2-[[benziloksifosfinil]oksi]-2-fenilprop-2-eniletiķskābes; 2-[[(2-piridil)metiloksifosfinil]oksi]glutārskābes; 2-[[(3-piridil)metiloksifosfinil]oksi]glutārskābes;

30 2-[[(4-piridil)metiloksifosfinil]oksi]glutārskābes; 2-[[(3-piridil)etiloksifosfinil]oksi]glutārskābes; 2-[[(3-piridil)propiloksifosfinil]oksi]glutārskābes;

2-[[(tetrahidrofuranil)metiloksifosfinil]oksi]glutārskābes;

2-[[(tetrahidrofuranil)etiloksifosfinil]oksi]glutārskābes;

2-[[(tetrahidrofuranil)propiloksifosfinil]oksi]glutārskābes;

2-[[(2-indolil)metiloksifosfinil]oksi]glutārskābes;

2-[[(3-indoliI)metiIoksifosfinil]oksi]glutārskābes;

2-[[(4-indolil)metiloksifosfinil]oksi]glutārskābes;

2-[[(3-indolil)etiloksifosfinil]oksi]glutārskābes;

2-[[(3-indolil)propiloksifosfinil]oksi]glutārskābes;

2-[[(2-tienil)metiloksifosfinil]oksiJglutārskābes;

2-[[(3-tienil)metiloksifosfinil]oksi]glutārskābes;

2-[[(4-tienil)metiloksifosfinil]oksi]glutārskābes;

2-[[(3-tienil)etiloksifosfinil]oksi]glutārskābes;

2-[[(3-tienil)propiloksifosfinil]oksi]glutārskābes;

2-[[(2-piridil)metiloksifosfinil]oksi]-2-feniletiķskābes;

2-[[(3-piridil)metiloksifosfinil]oksi]-2-feniletiķskābes;

2-[[(4-piridil)metiloksifosfinil]oksi]-2-feniletiķskābes;

2-[[(3-piridil)etiloksifosfinil]oksi]-2-feniletiķskābes;

2-[[(3-piridil)propiloksifosfinil]oksi]-2-feniletiķskābes;

2-[[(tetrahidrofuranil)metiloksifosfinil]oksi]-2-feniletiķskābes;

2-[[(tetrahidrofuranil)etiloksifosfinil]oksi]-2-feniletiķskābes;

2-[[(tetrahidrofuranil)propiloksifosfinil]oksi]-2-feniletiķskābes;

2-[[(2-indolil)metiloksifosfinil]oksi]-2-feniletiķskābes;

2-[[(3-indolil)metiloksifosfinil]oksi]-2-feniletiķskābes;

2-[[(4-indolil)metiloksifosfinil]oksi]-2-feniletiķskābes;

2-[[(3-indolil)etiloksifosfinil]oksi]-2-feniletiķskābes;

2-[[(3-indolil)propiloksifosfinil]oksi]-2-feniletiķskābes;

2-[[(2-tienil)metiloksifosfinil]oksi]-2-feniletiķskābes;

2-[[(3-tienil)metiloksifosfinil]oksi]-2-feniletiķskābes;

2-[[(4-tienil)metiloksifosfinil]oksi]-2-feniletiķskābes;

2-[[(3-tienil)etiloksifosfiniI]oksi]-2-feniletiķskābes;

2-[[(3-tienil)propiloksifosfinil]oksi]-2-feniletiķskābes;

2-[[benziloksifosfinil]oksi]-2-(2-piridil)metiletiķskābes;

2-[[benziloksifosfinil]oksi]-2-(3-piridil)metiletiķskābes;

2-[[benziloksifosfinil]oksi]-2-(4-piridil)metiletiķskābes;

2-[[benziloksifosfinil]oksi]-2-(3-piridil)etiletiķskābes;

2-[[benziloksifosfinil]oksi]-2-(3-piridil)propiletiķskābes;

5 2-[[benziloksifosfinil]oksi]-2-(tetrahidrofuranil)metiletiķskābes; 2-[[benziloksifosfinil]oksi]-2-(tetrahidrofuranil)etiletiķskābes; 2-[[benziloksifosfinil]oksi]-2-(tetrahidrofuranil)propiletiķskābes; 2-[[benziloksifosfinil]oksi]-2-(2-indolil)metiletiķskābes; 2-[[benziloksifosfinilJoksi]-2-(3-indolil)metiletiķskābes;

10 2-[[benziloksifosfinil]oksi]-2-(4-indolil)metiletiķskābes; 2-[[benziloksifosfinil]oksi]-2-(3-indolil)etiletiķskābes; 2-[[benziloksifosfinil]oksi]-2-(3-indolil)propiletiķskābes; 2-[[benziloksifosfinil]oksi]-2-(2-tienil)metiletiķskābes; 2-[[benziloksifosfinil]oksi]-2-(3-tienil)metiletiķskābes;

15 2-[[benziloksifosfinil]oksi]-2-(4-tienil)metiletiķskābes; 2-[[benziloksifosfiniI]oksi]-2-(3-tienil)etiletiķskābes; 2-[[benziloksifosfinil]oksi]-2-(3-tienil)propiletiķskābes; un farmaceitiski pieņemama sāls, hidrāta un vielu maisījuma.

59. Pielietojums saskaņā ar 57. punktu, kas atšķiras

20 ar to, ka NAALADāzes inhibitoru izvēlas no grupas, kas sastāv no: 2-[(benziloksifosfinil)oksi]glutārskābes;

2-[(feniloksifosfinil)oksi]glutārskābes;

2-[[((oksi)fenilmetil)oksifosfinil]oksi]glutārskābes;

2-[(butiloksifosfinil)oksi]glutārskābes;

25 2-[[(3-metilbenzil)oksifosfinil]oksi]glutārskābes; 2-[(3-fenilpropiloksifosfinil)oksi]glutārskābes; 2-[[(4-fluorfenil)oksifosfinil]oksi]glutārskābes; 2-[(metiloksifosfinil)oksi]glutārskābes;

2-[(feniletiloksifosfinil)oksi]glutārskābes;

30 2-[[(4-metilbenzil)oksifosfinil]oksi]glutārskābes; 2-[[(4-fluorbenzil)oksifosfinil]oksi]glutārskābes; 2-[[(4-metoksibenzil)oksifosfinil]oksi]glutārskābes;

2-[[(2-fluorbenzil)oksifosfinil]oksi]glutārskābes;

2-[[(pentafluorbenzil)oksifosfinil]oksi]glutārskābes;

2-[(fosfono)oksi]glutārskābes;

2-[[(3-trifluormetilbenzil)oksifosfinil]oksi]glutārskābes;

un farmaceitiski pieņemama sāls, hidrāta un vielu maisījuma.

60. Pielietojums saskaņā ar 53. punktu, kas atšķiras ar to, ka Fķ un R₂ ir alifātiskas grupas ar taisnu vai sazarotu virkni vai karbocikliskas grupas un X ir NR_rgrupa.

61. Pielietojums saskaņā ar 60. punktu, kas atšķiras ar to, ka NAALADāzes inhibitoru izvēlas no grupas, kas sastāv no: 2-[[metiloksifosfinil]amino]glutārskābes;

2-[[etiloksifosfinil]amino]glutārskābes;

2-[[propiloksifosfinil]amino]glutārskābes;

2-[[butiloksifosfinil]amino]glutārskābes;

2-[[cikloheksiloksifosfinil]amino]glutārskābes;

2-[[(cikloheksil)metiloksifosfinil]amino]glutārskābes;

2-[[feniloksifosfinil]amino]glutārskābes;

2-[[benziloksifosfinil]amino]glutārskābes;

2-[[feniletiloksifosfinil]amino]glutārskābes;

2-[[fenilpropiloksifosfinil]amino]glutārskābes;

2-[[fenilbutiloksifosfinil]amino]glutārskābes;

2-[[(4-metilbenzil)oksifosfinil]amino]glutārskābes;

2-[[(4-fluorbenzil)oksifosfiniljamino]glutārskābes;

2-[[(2-fluorbenzil)oksifosfinil]amino]glutārskābes;

2-[[(pentafluorbenzil)oksifosfinil]amino]glutārskābes;

2-[[(metoksibenzil)oksifosfinil]amino]glutārskābes;

2-[[(2,3,4-trimetoksifenil)oksifosfinil]amino]glutārskābes;

2-[[(1-naftil)oksifosfinil]amino]glutārskābes;

2-[[(2-naftil)oksifosfinil]amino]glutārskābes;

2-[[(1-naftil)metiloksifosfinil]amino]glutārskābes;

2-[[(2-naftil)metiloksifosfinil]amino]glutārskābes;

2-[[(1 -naftil)etiloksifosfinil]amino]glutārskābes;

2-[[(2-naftil)etiloksifosfinil]amino]glutārskābes;

2-[[(1-naftil)propiloksifosfinil]amino]glutārskābes;

2-[[(2-naftil)propiloksifosfinil]amino]glutārskābes;

2-[[(1-naftil)butiloksifosfinil]amino]glutārskābes;

2-[[(2-naftil)butiloksifosfinil]amino]glutārskābes;

2-[[(fenilprop-2-enil)oksifosfinil]amino]glutārskābes;

2-[[benziloksifosfinil]amino]glutārskābes;

2-[[(4-fluorfenil)oksifosfinil]amino]glutārskābes;

2-[[((oksi)feniImetil)oksifosfinil]amino]glutārskābes;

2-[[(3-metilbenzil)oksifosfinil]amino]glutārskābes;

2-[(fosfono)amino]glutārskābes;

2-[[(3-trifluormetilbenzil)oksifosfinil]amino]glutārskābes;

2-[[metiloksifosfinil]amino]-2-feniletiķskābes;

2-[[etiloksifosfiniljamino]-2-feniletiķskābes;

2-[[propiloksifosfinil]amino]-2-feniletiķskābes;

2-[[butiloksifosfinil]amino]-2-feniletiķskābes;

2-[[cikloheksiloksifosfinil]amino]-2-feniletiķskābes;

2-[[(cikloheksil)metiloksifosfinil]amino]-2-feniletiķskābes;

2-[[feniloksifosfinil]amino]-2-feniletiķskābes;

2-[[benziloksifosfinil]amino]-2-feniletiķskābes;

2-[[feniletiloksifosfinil]amino]-2-feniletiķskābes;

2-[[fenilpropiloksifosfinil]amino]-2-feniletiķskābes;

2-[[fenilbutiloksifosfinil]amino]-2-feniletiķskābes;

2-[[(2,3,4-trimetoksifenil)-3-oksifosfinil]amino]-2-feniletiķskābes;

2-[[(1-naftil)oksifosfinil]amino]-2-feniletiķskābes;

2-[[(2-naftil)oksifosfinil]amino]-2-feniletiķskābes;

2-[[(1 -naftil)metiloksifosfinil]amino]-2-feniletiķskābes; 2-[[(2-naftil)metiloksifosfinil]amino]-2-feniletiķskābes; 2-[[(1-naftil)etiloksifosfinil]amino]-2-feniletiķskābes; 2-[[(2-naftil)etiloksifosfinil]amino]-2-feniletiķskābes;

2-[[(1-naftil)butiloksifosfinil]amino]-2-feniletiķskābes;

2-[[(2-naftil)butiloksifosfinil]amino]-2-feniletiķskābes;

2-[[fenilprop-2-eniloksifosfinil]amino]-2-feniletiķskābes;

2-[[benziloksifosfinil]amino]-2-metiletiķskābes;

5 2-[[benziloksifosfinil]amino]-2-etiletiķskābes; 2-[[benziloksifosfinil]amino]-2-propiletiķskābes; 2-[[benziloksifosfinil]amino]-2-butiletiķskābes; 2-[[benziloksifosfinil]amino]-2-cikloheksiletiķskābes; 2-[[benziloksifosfinil]amino]-2-(cikloheksil)metiletiķskābes;

10 2-[[ben zi loks if osf in iljami n o]-2-f en i letiķskābes;

2-[[benziloksifosfinil]amino]-2-benziletiķskābes; 2-[[benziloksifosfinil]amino]-2-feniletiletiķskābes; 2-[[benziloksifosfinil]amino]-2-fenilpropiletiķskābes; 2-[[benziloksifosfinil]amino]-2-fenilbutiletiķskābes;

15 2-[[benziloksifosfinil]amino]-2-(2,3,4-trimetoksifenil)etiķskābes; 2-[[benziloksifosfinil]amino]-2-(1-naftil)etiķskābes; 2-[[benziloksifosfinil]amino]-2-(2-naftil)etiķskābes; 2-[[benziloksifosfinil]amino]-2-(1-naftii)metiletiķskābes; 2-[[benziloksifosfinil]amino]-2-(2-naftii)metiletiķskābes;

20 2-[[benziloksifosfinil]amino]-2-(1 -naftil)etiletiķskābes; 2-[[benziloksifosfinil]amino]-2-(2-naftil)etiletiķskābes; 2-[[benziloksifosfinil]amino]-2-(1-naftil)propiletiķskābes; 2-[[benziloksifosfinil]amino]-2-(2-naftil)propiletiķskābes; 2-[[benziloksifosfinil]amino]-2-(1-naftil)butiletiķskābes;

25 2-[[benziloksifosfinil]amino]-2-(2-naftil)butiletiķskābes; 2-[[benziloksifosfinil]amino]-2-feniiprop-2-eniietiķskābes; 2-[(metiloksifosfinil)amino]adipīnskābes;

2-[(benziloksjfosfinil)amino]adipīnskābes;

2-[(metiloksifosfinil)amino]pimelīnskābes;

30 2-[(benziloksifosfinil)amino]pimelīnskābes;

2-[(metiloksifosfinil)amino]heksāndikarbonskābes;

2-[(benziloksifosfinil)amino]heksāndikarbonskābes;

2-[(metiloksifosfinil)amino]azelaīnskābes;

2-[(benziloksifosfinil)amino]azelaīnskābes;

2-[(metiloksifosfinil)amino]sebacīnskābes;

2- [(benziloksifosfinil)amino]sebacīnskābes;

5 3-[[(2-piridil)metiloksifosfinil]amino]glutārskābes;

3- [[(3-piridil)metiloksifosfinil]amino]glutārskābes; 3-[[(4-piridil)metiloksifosfinil]amino]glutārskābes; 3-[[(3-piridil)etiloksifosfinil]amino]glutārskābes; 3-[[(3-piridil)propiloksifosfinil]amino]glutārskābes;

10 3-[[(tetrahidrofuranil)metiloksifosfinil]amino]glutārskābes; 3-[[(tetrahidrofuranil)etiloksifosfinil]amino]glutārskābes; 3-[[(tetrahidrofuranil)propiloksifosfinil]amino]glutārskābes; 3-[[(2-indolil)metiloksifosfinil]amino]glutārskābes; 3-[[(3-indolil)metiloksifosfinil]amino]glutārskābes;

15 3-[[(4-in dol i I) m eti loks if osf inil]amino]glutārskābes;

3-[[(3-indolil)etiloksifosfinil]amino]glutārskābes; 3-[[(3-indolil)propiloksifosfinil]amino]glutārskābes; 3-[[(2-tienil)metiloksifosfinil]amino]glutārskābes; 3-[[(3-tienil)metiloksifosfinil]amino]glutārskābes;

20 3-[[(4-tienil)metiloksifosfinil]amino]glutārskābes; 3-[[(3-tienil)etiloksifosfinil]amino]glutārskābes; 3-[[(3-tienil)propiloksifosfinil]amino]glutārskābes; 2-[[(2-piridil)metiloksifosfinil]amino]-2-feniletiķskābes; 2-[[(3-piridil)metiloksifosfinil]amino]-2-feniletiķskābes;

25 2-[[(4-piridii)metiloksifosfinil]amino]-2-feniletiķskābes; 2-[[(3-piridil)etiloksifosfinil]amino]-2-feniletiķskābes; 2-[[(3-piridil)propiloksifosfinil]amino]-2-feniletiķskābes; 2-[[(tetrahidrofuranil)metiloksifosfinil]amino]-2-feniletiķskābes; 2-[[(tetrahidrofuranil)etiloksifosfinil]amino]-2-feniletiķskābes;

30 2-[[(tetrahidrofuranil)propiloksifosfinil]amino]-2-feniletiķskābes; 2-[[(2-indolil)metiloksifosfinil]amino]-2-feniletiķskābes; 2-[[(3-indolil)metiloksifosfinil]amino]-2-feniletiķskābes;

2-[[(4-indolil)metiloksifosfinil]amino]-2-feniletiķskābes;

2-[[(3-indolil)etiloksifosfinil]amino]-2-feniletiķskābes;

2-[[(3-indolil)propiloksifosfinil]amino]-2-feniletiķskābes;

2-[[(2-tienil)metiloksifosfinil]amino]-2-feniletiķskābes;

2-[[(3-tienil)metiloksifosfinil]amino]-2-feniletiķskābes;

2-[[(4-tienil)metiloksifosfinil]amino]-2-feniletiķskābes;

2-[[(3-tienil)etiloksifosfinil]amino]-2-feniletiķskābes;

2-[[(3-tienil)propiloksifosfinil]amino]-2-feniletiķskābes;

2-[[benziloksifosfinil]amino]-2-(2-piridil)metiletiķskābes;

2-[[benziloksifosfinil]amino]-2-(3-piridil)metiletiķskābes;

2-[[benziloksifosfinil]amino]-2-(4-piridil)metiletiķskābes;

2-[[benziloksifosfinil]amino]-2-(3-piridil)etiletiķskābes;

2-[[benziloksifosfinil]amino]-2-(3-piridil)propiletiķskābes;

2-[[benziloksifosfinil]amino]-2-(tetrahidrofuranil)metiletiķskābes;

2-[[benziloksifosfiniljamino]-2-(tetrahidrofuranil)etiletiķskābes;

2-[[benziloksifosfinil]amino]-2-(tetrahidrofuranil)propiletiķskābes;

2-[[benziloksifosfinil]amino]-2-(2-indolil)metiletiķskābes;

2-[[benziloksifosfinil]amino]-2-(3-indolil)metiletiķskābes;

2-[[benziloksifosfinil]amino]-2-(4-indolil)metiletiķskābes;

2-[[benziloksifosfinil]amino]-2-(3-indolil)etiletiķskābes;

2-[[benziloksifosfinil]amino]-2-(3-indolil)propiletiķskābes;

2-[[benziloksifosfinil]amino]-2-(2-tienil)metiletiķskābes;

2-[[benziloksifosfinil]amino]-2-(3-tienil)metiletiķskābes;

2-[[benziloksifosfinil]amino]-2-(4-tienil)metiletiķskābes;

2-[[benziloksifosfinil]amino]-2-(3-tienil)etiletiķskābes;

2-[[benziloksifosfinil]amino]-2-(3-tienil)propiletiķskābes;

un farmaceitiski pieņemama sāls, hidrāta un vielu maisījuma.

62. Pielietojums saskaņā ar 60. punktu, kas atšķiras ar to, ka NAALADāzes inhibitoru izvēlas no grupas, kas sastāv no: 2-[(benziloksifosfinil)amino]glutārskābes; 2-[(feniloksifosfinil)amino]glutārskābes; 2-[[((oksi)fenilmetil)oksifosfinil]amino]glutārskābes;

2-[(butiloksifosfinil)amino]glutārskābes;

2-[[(3-metilbenzil)oksifosfinil]amino]glutārskābes;

2-[(3-fenilpropiloksifosfinil)amino]glutārskābes;

2-[[(4-fluorfenil)oksifosfinil]amino]glutārskābes;

2-[(metiloksifosfinil)amino]glutārskābes;

2-[(feniletiloksifosfinil)amino]glutārskābes;

2-[[(4-metilbenzil)oksifosfinil]amino]glutārskābes;

2-[[(4-fluorbenzil)oksifosfinil]amino]glutārskābes;

2-[[(4-metoksibenzil)oksifosfinil]aminojglutārskābes;

2-[[(2-fluorbenzil)oksifosfinil]amino]glutārskābes;

2-[[(pentafluorbenzil)oksifosfinil]amino]glutārskābes;

2-[(fosfono)amino]glutārskābes;

2-[[(3-trifluormetilbenzil)oksifosfinil]amino]glutārskābes;

un farmaceitiski pieņemama sāls, hidrāta vai vielu maisījuma.

63. Pielietojums saskaņā ar 53. punktu, kas atšķiras ar to, ka Rļ vai R₂ ir heterocikliska grupa un X ir CH₂-grupa.

64. Pielietojums saskaņā ar 63. punktu, kas atšķiras ar to, ka NAALADāzes inhibitoru izvēlas no grupas, kas sastāv no: 2-[[(2-piridil)oksifosfinil]metil]glutārskābes;

2-[[(3-piridil)oksifosfinil]metil]glutārskābes;

2-[[(4-piridil)oksifosfinil]metil]glutārskābes;

2-[[(tetrahidrofuranil)oksifosfinil]metil]glutārskābes;

2-[[(2-indolil)oksifosfinil]metil]glutārskābes;

2-[[(3-indolil)oksifosfinil]metil]glutārskābes;

2-[[(4-indolil)oksifosfinil]metil]glutārskābes;

2-[[(2-tienil)oksifosfinil]metil]glutārskābes;

2-[[(3-tienil)oksifosfinil]metil]glutārskābes;

2- [[(4-tienil)oksifosfinil]metil]glutārskābes;

3- [(2-piridil)oksifosfinil]-2-fenilpropionskābes;

3-[(3-piridil)oksifosfinil]-2-fenilpropionskābes;

3-[(4-piridil)oksifosfinil]-2-fenilpropionskābes;

3-[(tetrahidrofuranil)oksifosfinil]-2-fenilpropionskābes;

3-[(2-indolil)oksifosfinil]-2-fenilpropionskābes;

3-[(3-indolii)oksifosfinil]-2-fenilpropionskābes;

3-[(4-indolil)oksifosfinil]-2-fenilpropionskābes;

3-[(2-tienil)oksifosfinil]-2-fenilpropionskābes;

3-[(3-tienil)oksifosfinil]-2-fenilpropionskābes;

3-[(4-tienil)oksifosfinil]-2-fenilpropionskābes;

3-(benziloksifosfinil)-2-(2-piridil)propionskābes;

3-(benziloksifosfinil)-2-(3-piridil)propionskābes;

3-(benziloksifosfinil)-2-(4-piridil)propionskābes;

3-(benziloksifosfinil)-2-(tetrahidrofuranil)propionskābes;

3-(benziloksifosfinil)-2-(2-indolil)propionskābes;

3-(benziloksifosfinil)-2-(3-indolil)propionskābes;

3-(benziloksifosfinil)-2-(4-indolil)propionskābes;

3-(benziloksifosfinii)-2-(2-tienil)propionskābes;

3-(benziloksifosfinil)-2-(3-tienil)propionskābes;

3-(benziloksifosfinil)-2-(4-tienil)propionskābes;

un farmaceitiski pieņemama sāls, hidrāta vai vielu maisījuma.

65. Pielietojums saskaņā ar 63. punktu, kas atšķiras ar to, ka R, vai R₂ ir heterocikliska grupa un X ir skābekļa atoms.

66. Pielietojums saskaņā ar 65. punktu, kas atšķiras ar to, ka NAALADāzes inhibitoru izvēlas no grupas, kas sastāv no: 2-[[(2-piridil)oksifosfinii]oksi]glutārskābes;

2-[[(3-piridil)oksifosfinil]oksi]glutārskābes;

2-[[(4-piridil)oksifosfinil]oksi]glutārskābes;

2-[[(tetrahidrofuranil)oksifosfinil]oksi]glutārskābes;

2-[[(2-indolil)oksifosfinil]oksi]glutārskābes;

2-[[(3-indolil)oksifosfinil]oksi]glutārskābes;

2-[[(4-indolil)oksifosfinil]oksi]glutārskābes;

2-[[(2-tienil)oksifosfinil]oksi]glutārskābes;

2-[[(3-tienil)oksifosfinil]oksi]glutārskābes;

2-[[(4-tienil)oksifosfinil]oksi]glutārskābes;

2-[[(2-piridil)oksifosfinil]oksi]-2-feniletiķskābes;

2-[[(3-piridil)oksifosfinil]oksi]-2-feniletiķskābes;

2-[[(4-piridil)oksifosfinil]oksi]-2-feniletiķskābes;

2-[[(tetrahidrofuranil)oksifosfinil]oksi]-2-feniletiķskābes;

2-[[(2-indolil)oksifosfinil]oksi]-2-feniletiķskābes;

5 2-[[(3-indolil)oksifosfinil]oksi]-2-feniletiķskābes; 2-[[(4-indolil)oksifosfinil]oksi]-2-feniletiķskābes; 2-[[(2-tienil)oksifosfinil]oksi]-2-feniletiķskābes; 2-[[(3-tienil)oksifosfinil]oksi]-2-feniletiķskābes; 2-[[(4-tienil)oksifosfinil]oksi]-2-feniletiķskābes;

10 2-[[benziloksifosfinil]oksi]-2-(2-piridil)etiķskābes; 2-[[benziloksifosfinil]oksi]-2-(3-piridil)etiķskābes; 2-[[benziloksifosfinil]oksi]-2-(4-piridil)etiķskābes; 2-[[benziloksifosfinil]oksi]-2-(tetrahidrofuranil)etiķskābes; 2-[[benziloksifosfinil]oksi]-2-(2-indolil)etiķskābes;

15 2-[[benziloksifosfinil]oksi]-2-(3-indolil)etiķskābes; 2-[[benziloksifosfinil]oksi]-2-(4-indolil)etiķskābes; 2-[[benziloksifosfinil]oksi]-2-(2-tienil)etiķskābes; 2-[[benziloksifosfinil]oksi]-2-(3-tienil)etiķskābes; 2-[[benziloksifosfinil]oksi]-2-(4-tienil)etiķskābes;

20 un farmaceitiski pieņemama sāls, hidrāta vai vielu maisījuma.

67. Pielietojums saskaņā ar 53. punktu, kas atšķiras ar to, ka Rļ vai R₂ ir heterocikliska grupa un X ir NR^grupa.

68. Pielietojums saskaņā ar 67. punktu, kas atšķiras ar to, ka NAALADāzes inhibitoru izvēlas no grupas, kas sastāv no:

25 2-[[(2-piridil)oksifosfinil]amino]glutārskābes; 2-[[(3-piridil)oksifosfiniI]amino]glutārskābes; 2-[[(4-piridil)oksifosfinil]amino]glutārskābes; 2-[[(tetrahidrofuranil)oksifosfinil]amino]glutārskābes; 2-[[(2-indolil)oksifosfinil]amino]glutārskābes;

30 2-[[(3-indolil)oksifosfinil]amino]glutārskābes; 2-[[(4-indolil)oksifosfinil]amino]glutārskābes; 2-[[(2-tienil)oksifosfinil]amino]glutārskābes;

2-[[(3-tienil)oksifosfinil]amino]glutārskābes;

2-[[(4-tienil)oksifosfinil]amino]glutārskābes;

2-[[(2-piridil)oksifosfinil]amino]-2-feniletiķskābes;

2-[[(3-piridil)oksifosfinil]aminoj-2-feniletiķskābes;

5 2-[[(4-piridil)oksifosfinil]amino]-2-feniletiķskābes;

2-[[(tetrahidrofuranil)oksifosfinil]amino]-2-feniletiķskābes;

2-[[(2-indolil)oksifosfinil]amino]-2-feniletiķskābes;

2-[[(3-indolil)oksifosfinil]amino]-2-feniletiķskābes;

2-[[(4-indolil)oksifosfinil]amino]-2-feniletiķskābes;

1 o 2-[[(2-ti en il) oksif osf in il] am in o]-2-fen i leti ķskābes;

2-[[(3-tienil)oksifosfinil]amino]-2-feniIetiķskābes; 2-[[(4-tienil)oksifosfinil]amino]-2-feniletiķskābes; 2-[[benziloksifosfinil]amino]-2-(2-piridil)etiķskābes; 2-[[benziloksifosfinil]amino]-2-(3-piridil)etiķskābes;

15 2-[[benziloksifosfinil]amino]-2-(4-piridil)etiķskābes;

2-[[benziloksifosfinil]amino]-2-(tetrahidrofuranil)etiķskābes;

2-[[benziloksifosfinil]amino]-2-(2-indolil)etiķskābes;

2-[[benziloksifosfinil]amino]-2-(3-indolil)etiķskābes;

2-[[benziloksifosfinil]amino]-2-(4-indolil)etiķskābes;

20 2-[[benziloksifosfinil]amino]-2-(2-tienil)etiķskābes; 2-[[benziloksifosfinil]amino]-2-(3-tienil)etiķskābes; 2-[[benziloksifosfinil]amino]-2-(4-tienil)etiķskābes; un farmaceitiski pieņemama sāls, hidrāta vai vielu maisījuma.

LL *

* hiskvalskābes devas (M) log i-1-1-1-r

(euņs/uiuj/ siunzpnep seues>iruqes) eues6e|sai euipiuiij. - H£

FIG.2

- (Fosfometil) glutārskabes devas (M) log (euņs/uiiu/ suinzpnep seues>ļnjqes) eues69|S9ļ BUipiLUļi - h€

Kontrole

0,25 mkg / dienā ievadīts injekcijas veidā 0,25 mkg / dienā lietots polimēra veidā

FIG.3 (ε lulu) sujnd|e) siefepiA eiezpnv

FIG.4

ICC ϊω

OmOSCOincnCMr· to to o

(0 to to o

to i?

o

-q· to

Γ5

ΓΪ to

CM o

CM to o

to o

(%) euesoAizpzi (0 (0 c

Φ

Jū

OT

E σ>

OT

CC c

co >OT

O >

N

Ό

N (gUiui) siundjiļ efezpnv

Dienas pec žurkas inficēto šunu ievadīšanas