Thiolalkyl benzoic acid derivatives

Details Thiolalkyl benzoic acid derivatives Thiolalkyl benzoic acid derivatives

2002-05-30

2004-05-25

Killos, Paul J. (Department: 1625)

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

Organic compounds

Carboxylic acids and salts thereof

C514S317000

Reexamination Certificate

active

06740777

ABSTRACT:

The present 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, neuropathy, pain, compulsive disorders, prostate diseases, cancers, glaucoma, and retinal disorders.
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, 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
The present invention relates to a compound of formula Ia or a pharmaceutically acceptable equivalent:
wherein:
R
1
, R
2
, R
3
, and R
4
are independently hydrogen or C
1
-C
3
alkyl; and
A
1
, A
2
, A
3
, and A
4
are independently hydrogen, C
1
-C
9
alkyl, C
2
-C
9
alkenyl, C
2
-C
9
alkynyl, aryl, heteroaryl, carbocycle, heterocycle, halo, hydroxy, sulfhydryl, nitro, amino, cyano, isocyano, thiocyano, isothiocyano, formamido, thioformamido, sulfo, sulfino, C
1
-C
9
alkylsulfonyl, C
1
-C
9
alkoxy, C
2
-C
9
alkenoxy, phenoxy, or benzyloxy,
wherein said alkyl, alkenyl, alkynyl, aryl, heteroaryl, carbocycle, heterocycle, alkoxy, alkenoxy, phenoxy, and benzyloxy are independently unsubstituted or substituted with one or more substituent(s).
In one embodiment, R
1
, R
2
, R
3
, R
4
, A
2
, A
3
, and A
4
are hydrogen; and A
1
is hydrogen, —(CH
2
)
n
—W, or —Y—(CH
2
)
n
—W, wherein: n is 0-3; Y is O, S, or NR wherein R is hydrogen or C1-C4 alkyl; and W is C1-C6 alkyl or phenyl, wherein W is unsubstituted or substituted with C1-C4 alkyl, C1-C4 alkoxy, carboxy, or halo.
The present invention further relates to a compound of formula Ib or a pharmaceutically acceptable equivalent:
wherein A
1
, A
2
, A
3
and A
4
are independently hydrogen, C
1
-C
9
alkyl, C
2
-C
9
alkenyl, C
2
-C
9
alkynyl, aryl, heteroaryl, carbocycle, heterocycle, halo, hydroxy, sulfhydryl, nitro, amino, cyano, isocyano, thiocyano, isothiocyano, formamido, thioformamido, sulfo, sulfino, C
1
-C
9
alkylsulfonyl, C
1
-C
9
alkoxy, C
2
-C
9
alkenoxy, phenoxy, or benzyloxy,
wherein said alkyl, alkenyl, alkynyl, aryl, heteroaryl, carbocycle, heterocycle, alkoxy, alkenoxy, phenoxy, and benzyloxy are independently unsubstituted or substituted with one or more substituent(s),
wherein if A
1
is chloro, fluoro, amino, or thiomethyl then A
2
, A
3
, and A
4
may not all be hydrogen,
and wherein at least one of A
1
, A
2
, A
3
, and A
4
is not hydrogen.
In one embodiment, A
2
, A
3
, and A
4
are hydrogen; and A
1
is —(CH
2
)
n
—Ar or —Y—(CH
2
)
n
—Ar, wherein n is 0-3, Y is O, S, or NR wherein R is hydrogen or C1-C4 alkyl, and Ar is phenyl, unsubstituted or substituted with C1-C4 alkyl, carboxy, or halo.
The present invention further relates to a compound of formula I:
or a pharmaceutically acceptable equivalent, wherein:
X is —(CR
1
R
2
)
n
SH, —O(CR
1
R
2
)
2
SH, —S(CR
1
R
2
)
2
SH, or —NR(CR
1
R
2
)
2
SH;
n is 1-3; and
R, R
1
, R
2
, A
1
, A
2
, A
3
and A
4
are independently hydrogen, C
1
-C
9
alkyl, C
2
-C
9
alkenyl, C
2
-C
9
alkynyl, aryl, heteroaryl, carbocycle, heterocycle, halo, hydroxy, sulfhydryl, nitro, amino, cyano, isocyano, thiocyano, isothiocyano, formamido, thioformamido, sulfo, sulfino, C
1
-C
9
alkylsulfonyl, C
1
-C
9
alkoxy, C
2
-C
9
alkenoxy, phenoxy, or benzyloxy,
wherein said alkyl, alkenyl, alkynyl, aryl, heteroaryl, carbocycle, heterocycle, alkoxy, alkenoxy, phenoxy, and benzyloxy are independently unsubstituted or substituted with one or more substituent(s).
Additionally, the present invention relates to a method for inhibiting NAALADase enzyme activity, detecting diseases where NAALADase levels are altered, effecting neuronal activity, effecting TGF-&bgr;, activity, inhibiting angiogenesis, or treating glutamate abnormalities, neuropathy, pain, compulsive disorders, prostate diseases, cancers, glaucoma, or retinal disorders, comprising administering to a mammal in need of such inhibition, treatment or effect, an effective amount of a compound of formula I, Ia, or Ib, as defined above.
The present invention further relates to a 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, Ia, or Ib, 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.
The present 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, Ia, or Ib, 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, the present 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, Ia, or Ib, as defined above, labeled with a marker.
Finally, the present invention relates to a pharmaceutical composition comprising:
(i) an effective amount of a compound of formula I, Ia, or Ib, as described above; and
(ii) a pharmaceutically acceptable carrier.


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