Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Phosphorus containing other than solely as part of an...
Reexamination Certificate
1999-04-26
2001-09-11
Ambrose, Michael G. (Department: 1613)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Phosphorus containing other than solely as part of an...
C514S114000, C558S169000, C558S179000, C562S010000
Reexamination Certificate
active
06288046
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to phosphonic acid derivatives that inhibit N-Acetylated &agr;-Linked Acidic Dipeptidase (NAALADase) enzyme activity, pharmaceutical compositions comprising such derivatives, and methods of using such derivatives to inhibit NAALADase activity, to treat a glutamate abnormality and to treat a prostate disease in an animal.
2. Description of the Prior Art
Glutamate Abnormalities
Glutamate has been implicated in various neurological diseases and conditions, including epilepsy, stroke, Alzheimer's disease, Parkinson's Disease, Amyotrophic Lateral Sclerosis (ALS), Huntington's Disease, schizophrenia, chronic pain, ischemia and neuronal loss following hypoxia, hypoglycemia, ischemia, trauma and nervous insult. Neurons release glutamate in great quantities when they are deprived of oxygen, as may occur during an ischemic brain insult such as a stroke or a heart attack. This excess release of glutamate in turn causes over-stimulation (excitotoxicity) of NMDA, AMPA, Kainate and MGR receptors. When glutamate binds to these receptors, ion channels in the cell membranes of the neurons open, permitting flows of ions across the cell membranes, e.g., Ca
2+
and Na
+
into the cells and K
+
out of the cells. These flows of ions, especially the influx of Ca
2+
, cause over-stimulation of the neurons. The over-stimulated neurons secrete more glutamate, creating a domino-effect which ultimately results in cell death via the production of proteases, lipases and free radicals.
Attempts to prevent excitotoxicity by blocking NMDA, AMPA, Kainate and MGR receptors have proven difficult because each receptor has multiple sites to which glutamate may bind. Many of the compositions that are effective in blocking the receptors are also toxic to animals. As such, there is currently no known effective treatment for glutamate abnormalities.
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 rate 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 rates are expected as men live longer and the disease has more time to progress.
In 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 itrium labelled PSMA antibodies, have been described and examined clinically for the diagnosis and treatment of prostate cancer. PSMA is expressed in prostatic ductal epithelium and is present in seminal plasma, prostatic fluid and urine. 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. For example, it has been demonstrated that intra-hippocampal injections of NAAG elicit prolonged seizure activity. More recently, it was reported that rats genetically prone to epileptic seizures have a persistent increase in their basal level of NAALADase activity. These observations support the hypothesis that increased availability of synaptic glutamate elevates seizure susceptibility, and suggest that NAALADase inhibitors may provide anti-epileptic activity.
NAAG and NAALADase have also been implicated in the pathogenesis of ALS and in the pathologically similar animal disease called Hereditary Canine Spinal Muscular Atrophy (HCSMA). It has been shown that concentrations of NAAG and its metabolites—NAA, glutamate and aspartate—are elevated two—to three-fold in the cerebrospinal fluid of ALS patients and HCSMA dogs. Additionally, NAALADase activity is significantly increased (two- to three-fold) in post-mortem spinal cord tissue from ALS patients and HCSMA dogs. As such, NAALADase inhibitors may be clinically useful in curbing the progression of ALS if increased metabolism of NAAG is responsible for the alterations of CSF levels of these acidic amino acids and peptides.
Abnormalities in NAAG levels and NAALADase activity have also been documented in post-mortem schizophrenic brain, specifically in the prefrontal and limbic brain regions.
The findings described above suggest that NAALADase inhibitors could be useful in treating glutamate abnormalities. In fact, the results of studies conducted by the present inventors confirm that NAALADase inhibitors are not only effective in treating glutamate abnormalities, but also effective in treating prostate diseases, particularly prostate cancer. Although the cancer data relate to prostate cancer cells, NAALADase inhibitors are expected to be equally effective in treating cancer of other tissues where NAALADase enzyme reside, such as the brain, kidney 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, metal chelators such as EGTA and EDTA, and peptide analogs such as quisqualic acid and &bgr;-NAAG. Accordingly, a need exists for more NAALADase inhibitors to be identified and used in treatments of glutamate abnormalities and prostate diseases.
SUMMARY OF THE INVENTION
The present invention relates to phosphonic acid derivatives that inhibit NAALADase enzyme activity, pharmaceutical compositions comprising such derivatives, and methods of using such derivatives to inhabit NAALADase activity, to treat a glutamate abnormality and to treat a prostate disease in an animal.
Specifically, the present invention relates to a compound of formula I:
or a pharmaceutically acceptable salt or hydrate thereof, wherein:
Y is selected from the group consisting of CR
1
R
2
, NR
3
and O;
X is selected from the group consisting of hydrogen, C
1
-C
9
straight or branched chain alkyl, C
2
-C
9
straight or branched chain alkenyl, C
3
-C
8
cycloalkyl, C
5
-C
7
cycloalkenyl and Ar, wherein said X is unsubstituted or substituted with carboxy, C
3
-C
8
cycloalkyl, C
5
-C
7
cycloalkenyl, halo, hydroxy, nitro, trifluoromethyl, C
1
-C
6
straight or branched chain alkyl, C
2
-C
6
straight or branched chain alkenyl, C
1
-C
4
alkoxy, C
2
-C
4
alkenyloxy, phenoxy, benzyloxy, amino, Ar or mixtures thereof;
R, R
1
, R
2
and R
3
are independently selected from the group consisting of hydrogen, C
1
-C
9
straight or branched chain alkyl, C
2
-C
9
straight or branched chain alkenyl, C
3
-C
8
cycloalkyl, C
5
-C
7
cycloalkenyl and Ar, wherein said R, R
1
, R
2
and R
3
are independently unsubstituted or substituted with C
3
-C
8
cycloalkyl, C
5
-C
7
cycloalkenyl, halo, hydroxy, nitro, trifluoromethyl, C
1
-C
6
straight or branched chain alkyl, C
2
-C
6
straight or branched chain alkenyl, C
1
-C
4
alkoxy, C
2
-C
4
alkenyloxy, phenoxy, benzyloxy, amino, Ar or mixtures thereof, provided that R is not hydrogen when X is hydrogen, carboxymethyl or carboxyethyl; and
Ar is selected from the group consisting of 1-naphthyl, 2-naphthyl, 2-indolyl, 3-indolyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, benzyl and phenyl, wherein said Ar has one to three substituent(s) independently selected from the group consisting of hydrogen, halo, hydroxy, nitro, trifluoromethyl, C
1
-C
6
straight or branched chain alkyl, C
2
-C
6
straight or branched chain alkenyl, C
1
-C
4
alkoxy, C
2
-C
4
alkenyloxy, phenoxy, benzyloxy, amino and mixtures thereof.
The present invention also relates to a pharmaceutical composition comprising:
(i) a therapeutically effective amount of the com
Jackson Paul F.
Maclin Keith M.
Slusher Barbara S.
Tays Kevin L.
Ambrose Michael G.
Guilford Pharmaceuticals Inc.
Lyon & Lyon LLP
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