Thiol-based NAALADase inhibitors

Details Thiol-based NAALADase inhibitors Thiol-based NAALADase inhibitors

2002-01-17

2003-07-01

Davis, Brian (Department: 1621)

Organic compounds -- part of the class 532-570 series

Organic compounds

Carboxylic acids and salts thereof

C562S429000, C562S431000, C562S432000

Reexamination Certificate

active

06586623

ABSTRACT:

This invention relates to new compounds, pharmaceutical compositions and diagnostic kits comprising such compounds, and methods of using such compounds for inhibiting NAALADase enzyme activity, detecting diseases where NAALADase levels are altered, effecting neuronal activity, effecting TGF-&bgr; activity, inhibiting angiogenesis, and treating glutamate abnormalities, diabetic neuropathy, pain, compulsive disorders, prostate diseases, cancers and glaucoma.
The NAALADase enzyme, also known as prostate specific membrane antigen (“PSM” or “PSMA”) and human glutamate carboxypeptidase II (“GCP II”), catalyzes the hydrolysis of the neuropeptide N-acetyl-aspartyl-glutamate (“NAAG”) to N-acetyl-aspartate (“NAA”) and glutamate. Based upon amino acid sequence homology, NAALADase has been assigned to the M28 family of peptidases.
Studies suggest NAALADase inhibitors may be effective in treating ischemia, spinal cord injury, demyelinating diseases, Parkinson's disease, Amyotrophic Lateral Sclerosis (“ALS”), alcohol dependence, nicotine dependence, cocaine dependence, cancer, diabetic neuropathy, pain and schizophrenia, and in inhibiting angiogenesis. In view of their broad range of potential applications, a need exists for new NAALADase inhibitors and pharmaceutical compositions comprising such compounds.
SUMMARY OF THE INVENTION
This invention relates to a compound of formula I
or a pharmaceutically acceptable equivalent of said compound, wherein:
R
1
, R
2
, R
3
, R
4
, R
5
, R
6
, R
7
and R
8
are independently hydrogen or C
1
-C
3
alkyl;
A
1
, A
2
, A
3
and A
4
are independently hydrogen, C
1
-C
6
alkyl, C
1
-C
6
alkoxy, halo, nitro, phenyl, phenoxy, benzyl, benzyloxy or —COOH, or any adjacent two of A
2
, A
3
and A
4
form with the benzene ring a fused 5- or 6-membered carbocyclic or heterocyclic aromatic ring, said heterocyclic aromatic ring containing 1 or 2 oxygen, nitrogen and/or sulfur heteroatom(s).
This invention further relates to a compound of formula II
or a pharmaceutically acceptable equivalent of said compound, wherein:
R
1
, R
2
, R
3
, R
4
, R
5
, R
6
, R
7
and R
8
are independently hydrogen or C
1
-C
3
alkyl; and
A
1
, A
2
, A
3
, A
4
and A
5
are independently hydrogen, C
1
-C
6
alkyl, C
1
-C
6
alkoxy, C
1
-C
3
perhaloalkyl, phenyl, phenoxy, benzyl, benzyloxy, hydroxy, halo, cyano, nitro, —SO
2
R
9
, —(C═O)NR
9
R
10
, —(C═O)NR
9
(CH
2
)
n
COOH, —NR
9
(C═O)R
10
, —(CH
2
)
n
COOH or —COOH, or any adjacent two of A
1
, A
2
, A
3
, A
4
and A
5
form with the benzene ring a fused 5- or 6-membered carbocyclic or heterocyclic aromatic ring, said heterocyclic aromatic ring containing 1 or 2 oxygen, nitrogen and/or sulfur heteroatom(s);
R
9
and R
10
are independently hydrogen, C
1
-C
6
alkyl, phenyl or benzyl; and
n is 1-3;
provided that if A
1
, A
3
and A
5
are independently hydrogen, C
1
-C
6
alkyl, C
1
-C
6
alkoxy, halo, nitro, phenyl, phenoxy, benzyl, benzyloxy or —COOH, then neither A
2
nor A
4
are —COOH; and provided that if any adjacent two of A
3
, A
4
and A
5
form with the benzene ring a fused 5- or 6-membered carbocyclic or heterocyclic aromatic ring, said heterocyclic aromatic ring containing 1 or 2 oxygen, nitrogen and/or sulfur heteroatom(s), then A
2
is not —COOH.
This invention also relates to a compound of formula III
or a pharmaceutically acceptable equivalent of said compound, wherein:
X and Y are independently —CR
5
R
6
—, —O—, —S— or —NR—, provided that at least one of X and Y is/are —CR
5
R
6
—;
A
1
, A
2
, A
3
, A
4
and A
5
are independently hydrogen, C
1
-C
9
alkyl, C
2
-C
9
alkenyl, C
2
-C
9
alkynyl, aryl, heteroaryl, carbocycle, heterocycle, C
1
-C
9
alkoxy, C
2
-C
9
alkenyloxy, phenoxy, benzyloxy, hydroxy, halo, nitro, cyano, isocyano, —COOR
7
, —COR
7
, —NR
7
R
8
, —SR
7
, —SOR
7
, —SO
2
R
7
, —SO
2
(OR
7
), —(C═O)NR
7
R
8
, (C═O)NR
7
(CH
2
)
n
COOH, —NR
7
(C═O)R
8
or —(CH
2
)
n
COOH, or any adjacent two of A
1
, A
2
, A
3
, A
4
and A
5
form with the benzene ring a fused ring that is saturated or unsaturated, aromatic or non-aromatic, and carbocyclic or heterocyclic, said heterocyclic ring containing 1 or 2 oxygen, nitrogen and/or sulfur heteroatom(s);
n is 1-3;
R, R
1
, R
2
, R
3
, R
4
, R
5
, R
6
, R
7
and R
8
are independently hydrogen, C
1
-C
9
alkyl, C
2
-C
9
alkenyl, C
2
-C
9
alkynyl, aryl, heteroaryl, carbocycle or heterocycle; and
said alkyl, alkenyl, alkynyl, aryl, heteroaryl, carbocycle, heterocycle, alkoxy, alkenyloxy, phenoxy, benzyloxy, and fused ring are independently unsubstituted or substituted with one or more substituent(s);
provided that if A
1
, A
2
and A
3
are each hydrogen, and A
4
and A
5
are each —COOH, then A
4
is ortho to A
5
; and provided that if Y is —CR
5
R
6
—, then at least one of A
1
, A
2
, A
3
, A
4
and A
5
is/are independently phenoxy, benzyloxy, aryl, heteroaryl, carbocycle or heterocycle that is substituted with one or more substituent(s).
Additionally, this invention relates to method for inhibiting NAALADase enzyme activity, treating a glutamate abnormality, effecting a neuronal activity, treating a prostate disease, treating cancer, inhibiting angiogenesis or effecting a TGF-&bgr; activity, comprising administering to a mammal in need of such inhibition, treatment or effect, an effective amount of a compound of formula I, II or III, as described above.
This invention further relates to method for detecting a disease, disorder or condition where NAALADase levels are altered, comprising:
(i) contacting a sample of bodily tissue or fluid with a compound of formula I, II or III, as defined above, wherein said compound binds to any NAALADase in said sample; and
(ii) measuring the amount of any NAALADase bound to said sample, wherein the amount of NAALADase is diagnostic for said disease, disorder or condition.
This invention also relates to a method for detecting a disease, disorder or condition where NAALADase levels are altered in an animal or a mammal, comprising:
(i) labeling a compound of formula I, II or III, as defined above, with an imaging reagent;
(ii) administering to said animal or mammal an effective amount of the labeled compound;
(iii) allowing said labeled compound to localize and bind to NAALADase present in said animal or mammal; and
(iv) measuring the amount of NAALADase bound to said labeled compound, wherein the amount of NAALADase is diagnostic for said disease, disorder or condition.
Additionally, this invention further relates to a diagnostic kit for detecting a disease, disorder or condition where NAALADase levels are altered, comprising a compound of formula I, II or III, as defined above, labeled with a marker.
Finally, this invention relates to a pharmaceutical composition comprising:
(i) an effective amount of a compound of formula I, II or III, as described above; and
(ii) a pharmaceutically acceptable carrier.


REFERENCES:
patent: WO 98/53812 (1998-12-01), None
patent: WO 00/01668 (2000-01-01), None
patent: WO 01/91738 (2001-12-01), None
patent: WO 01/92273 (2001-12-01), None
patent: WO 01/92274 (2001-12-01), None
Suh et al., “Zn(II)-Chelating Inhibitors of Carboxypeptidase A”,Bioorganic&Medicinal Chemistry Letters, Mar. 16, 1995, pp. 585-588, vol. 5, No. 6, Elsevier Science Ltd., Amsterdam, NL.

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