US2001044459A1PendingUtilityA1
Hydroxamic acid derivatives
Priority: Apr 4, 1997Filed: Jun 15, 2001Published: Nov 22, 2001
Est. expiryApr 4, 2017(expired)· nominal 20-yr term from priority
A61P 43/00A61P 9/10A61P 35/00A61P 25/14A61P 25/08A61P 25/04A61P 25/16A61P 25/18A61P 25/28A61P 21/00A61P 13/08A61K 31/661C07F 9/301A61K 31/194A61K 38/05A61K 38/06
50
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Claims
Abstract
The present invention relates to hydroxamic acid derivatives that inhibit N-Acetylated α-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.
Claims
exact text as granted — not AI-modifiedWe claim:
1 . A compound of formula I:
or a pharmaceutically acceptable salt or hydrate thereof, wherein:
X is
Y is CR 1 R 2 , NR 3 or O;
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; 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, said Ar having 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 and amino.
2 . The compound of claim 1 , wherein at least one of said R, R 1 , R 2 and R 3 is/are independently 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 a combination thereof.
3 . The compound of claim 1 , wherein Y is CH 2 .
4 . The compound of claim 3 , wherein X is
5 . The compound of claim 4 , wherein R is selected from the group consisting of hydrogen, C 1 -C 4 straight or branched chain alkyl, 4-pyridyl, benzyl and phenyl, said R having one to three substituent(s) selected from the group consisting of hydrogen, 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 and Ar.
6 . The compound of claim 5 , which is selected from the group consisting of:
2-[[(N-hydroxy)carbamoyl]methyl]pentanedioic acid;
2-[[(N-hydroxy-N-methyl)carbamoyl]methyl]pentanedioic acid;
2-[[(N-butyl-N-hydroxy)carbamoyl]methyl]pentanedioic acid;
2-[[(N-benzyl-N-hydroxy)carbamoyl]methyl]pentanedioic acid;
2-[[(N-hydroxy-N-phenyl)carbamoyl]methyl]pentanedioic acid;
2-[[(N-hydroxy-N-2-phenylethyl)carbamoyl]methyl]pentanedioic acid;
2-[[(N-ethyl-N-hydroxy)carbamoyl]methyl]pentanedioic acid;
2-[[(N-hydroxy-N-propyl)carbamoyl]methyl]pentanedioic acid;
2-[[(N-hydroxy-N-3-phenylpropyl)carbamoyl]methyl]pentanedioic acid; and
2-[[((N-hydroxy-N-4-pyridyl)carbamoyl]methyl]pentanedioic acid.
7 . The compound of claim 3 , wherein X is
8 . The compound of claim 7 , wherein R is selected from the group consisting of hydrogen, C 1 -C 4 straight or branched chain alkyl, 4-pyridyl, benzyl and phenyl, said R having one to three substituent(s) selected from the group consisting of hydrogen, 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 and Ar.
9 . The compound of claim 8 , which is selected from the group consisting of:
2-[[(N-hydroxy)carboxamido]methyl]pentanedioic acid;
2-([N-hydroxy(methyl)carboxamido]methyl]pentanedioic acid;
2-[(N-hydroxy(benzyl)carboxamido]methyl]pentanedioic acid;
2-[(N-hydroxy(phenyl)carboxamido]methyl]pentanedioic acid;
2-[[N-hydroxy(2-phenylethyl)carboxamido]methyl]pentanedioic acid;
2-[[N-hydroxy(ethyl)carboxamidolmethyl]pentanedioic acid;
2-[[N-hydroxy(propyl)carboxamido]methyl]pentanedioic acid;
2[[N-hydroxy (3-phenylpropyl)carboxamido]methyl]pentanedioic acid; and
2-[[N-hydroxy(4-pyridyl)carboxamido]methyl]pentanedioic acid.
10 . A pharmaceutical composition comprising:
(i) a therapeutically effective amount of the compound of claim 1 ; and (ii) a pharmaceutically acceptable carrier.
11 . The pharmaceutical composition of claim 10 , wherein in said compound, at least one of said R, R 1 , R 2 and R 3 is/are independently substituted with C 3 -C 8 cycloalkyl, C 5 -C 7 cycloalkenyl, hydroxy, halo, 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 a combination thereof.
12 . The pharmaceutical composition of claim 10 , wherein in said compound, Y is CH 2 .
13 . The pharmaceutical composition of claim 12 , wherein in said compound, X is
14 . The pharmaceutical composition of claim 13 , wherein in said compound, R is selected from the group consisting of hydrogen, C 1 -C 4 straight or branched chain alkyl, 4-pyridyl, benzyl and phenyl, said R having one to three substituent(s) selected from the group consisting of hydrogen, C 3 -C 8 cycloallkyl, 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 and Ar.
15 . The pharmaceutical composition of claim 14 , wherein said compound is selected from the group consisting of:
2-[[(N-hydroxy)carbamoyl]methyl]pentanedioic acid;
2-[[(N-hydroxy-N-methyl)carbamoyl]methyl]pentanedioic acid;
2-[[(N-butyl-N-hydroxy)carbamoyl]methyl]pentanedioic acid;
2-[[(N-benzyl-N-hydroxy)carbamoyl]methyl]pentanedioic acid;
2-[[(N-hydroxy-N-phenyl)carbamoyl]methyl]pentanedioic acid;
2-[[(N-hydroxy-N-2-phenylethyl)carbamoyl]methyl]pentanedioic acid;
2-[[(N-ethyl-N-hydroxy)carbamoyl]methyl]pentanedioic acid;
2-[[(N-hydroxy-N-propyl)carbamoyl]methyl]pentanedioic acid;
2-[[(N-hydroxy-N-3-phenylpropyl)carbamoyl]methyl]pentanedioic acid; and
2-[[(N-hydroxy-N-4-pyridyl)carbamoyl]methyl]pentanedioic acid.
16 . The pharmaceutical composition of claim 12 , wherein in said compound, X is
17 . The pharmaceutical composition of claim 16 , wherein in said compound, R is selected from the group consisting of hydrogen, C 1 -C 4 straight or branched chain alkyl, 4-pyridyl, benzyl and phenyl, said R having one to three substituent(s) selected from the group consisting of hydrogen, 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 and Ar.
18 . The pharmaceutical composition of claim 17 , wherein said compound is selected from the group consisting of:
2-[[(N-hydroxy)carboxamido]methyl]pentanedioic acid;
2-[[N-hydroxy(methyl)carboxamido]methyl]pentanedioic acid;
2-[[N-hydroxy(benzyl)carboxamido]methyl]pentanedioic acid;
2- [[N-hydroxy(phenyl)carboxamido]methyl]pentanedioic acid;
2-[[N-hydroxy(2-phenylethyl)carboxamido]methyl]pentanedioic acid;
2-[[N-hydroxy(ethyl)carboxamido]methyl]pentanedioic acid;
2-[[N-hydroxy(propyl)carboxamido]methyl]pentanedioic acid;
2-[[N-hydroxy(3-phenylpropyl)carboxamido]methyl]pentanedioic acid; and
2-[[N-hydroxy(4-pyridyl)carboxamido]methyl]pentanedioic acid.
19 . The pharmaceutical composition of claim 10 , further comprising a therapeutic agent selected from the group consisting of therapeutic hormones, chemotherapeutic agents, monoclonal antibodies, antiangiogenesis agents, radiolabelled compounds, antineoplastic agents and mixtures thereof.
20 . The pharmaceutical composition of claim 10 , wherein said compound is present in an amount that is effective for inhibiting NAALADase activity in an animal, treating a glutamate abnormality in an animal or treating a prostate disease in an animal.
21 . A method of inhibiting NAALADase enzyme activity in an animal, comprising administering an effective amount of the compound of claim 1 to said animal.
22 . The method of claim 21 , wherein in said compound, Y is CH 2 .
23 . The method of claim 22 , wherein in said compound, X is
24 . The method of claim 23 , wherein in said compound, R is selected from the group consisting of hydrogen, C 1 -C 4 straight or branched chain alkyl, 4-pyridyl, benzyl and phenyl, said R having one to three substituent(s) selected from the group consisting of hydrogen, 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 and Ar.
25 . The method of claim 24 , wherein said compound is selected from the group consisting of:
2-[[(N-hydroxy)carbamoyl]methyl]pentanedioic acid;
2-[[(N-hydroxy-N-methyl)carbamoyl]methyl]pentanedioic acid;
2-[[(N-butyl-N-hydroxy)carbamoyl]methyl]pentanedioic acid;
2-[[(N-benzyl-N-hydroxy)carbamoyl]methyl]pentanedioic acid;
2-[[(N-hydroxy-N-phenyl)carbamoyl]methyl]pentanedioic acid;
2-[(N-hydroxy-N-2-phenylethyl)carbamoyl]methyl]pentanedioic acid;
2-[(N-ethyl-N-hydroxy)carbamoyl]methyl]pentanedioic acid;
2-[[(N-hydroxy-N-propyl)carbamoyl]methyl]pentanedioic acid;
2-[[(N-hydroxy-N-3-phenylpropyl)carbamoyl]methyl]pentanedioic acid; and
2-[[(N-hydroxy-N-4-pyridyl)carbamoyl]methyl]pentanedioic acid.
26 . The method of claim 22 , wherein in said compound, X is
27 . The method of claim 26 , wherein in said compound, R is selected from the group consisting of hydrogen, C 1 -C 4 straight or branched chain alkyl, 4-pyridyl, benzyl and phenyl, said R having one to three substituent(s) selected from the group consisting of hydrogen, 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 and Ar.
28 . The method of claim 27 , wherein said compound is selected from the group consisting of:
2-[[(N-hydroxy)carboxamido]methyl]pentanedioic acid;
2-[[N-hydroxy (methyl)carboxamido]methyl]pentanedioic acid;
2-[[N-hydroxy(benzyl)carboxamido]methyl]pentanedioic acid;
2-[[N-hydroxy(phenyl)carboxamido]methyl]pentanedioic acid;
2-[[N-hydroxy(2-phenylethyl)carboxamido]methyl]pentanedioic acid;
2-([N-hydroxy(ethyl)carboxamido]methyl]pentanedioic acid;
2-[[N-hydroxy(propyl)carboxamido]methyl]pentanedioic acid;
2-[[N-hydroxy(3-phenylpropyl)carboxamido]methyl]pentanedioic acid; and
2-[[N-hydroxy(4-pyridyl)carboxamido]methyl]pentanedioic acid.
29 . A method of treating a glutamate abnormality in an animal, comprising administering an effective amount of the compound of claim 1 to said animal.
30 . The method of claim 29 , wherein in said compound, Y is CH 2 .
31 . The method of claim 30 , wherein in said compound, X is
32 . The method of claim 31 , wherein in said compound, R is selected from the group consisting of hydrogen, C 1 -C 4 straight or branched chain alkyl, 4-pyridyl, benzyl and phenyl, said R having one to three substituent(s) selected from the group consisting of hydrogen, 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 and Ar.
33 . The method of claim 32 , wherein said compound is selected from the group consisting of:
2-[[(N-hydroxy)carbamoyl]methyl]pentanedioic acid;
2-[[(N-hydroxy-N-methyl)carbamoyl]methyl]pentanedioic acid;
2-[[(N-butyl-N-hydroxy)carbamoyl]methyl]pentanedioic acid;
2-[[(N-benzyl-N-hydroxy)carbamoyl]methyl]pentanedioic acid;
2-[[(N-hydroxy-N-phenyl)carbamoyl]methyl]pentanedioic acid;
2-[[(N-hydroxy-N-2 -phenylethyl)carbamoyl]methyl]pentanedioic acid;
2-[((N-ethyl-N-hydroxy)carbamoyl]methyl]pentanedioic acid;
2-[[(N-hydroxy-N-propyl)carbamoyl]methyl]pentanedioic acid;
2-[[(N-hydroxy-N-3-phenylpropyl)carbamoyl]methyl]pentanedioic acid; and
2-[[(N-hydroxy-N-4-pyridyl)carbamoyl]methyl]pentanedioic acid.
34 . The method of claim 30 , wherein in said compound, X is
35 . The method of claim 34 , wherein in said compound, R is selected from the group consisting of hydrogen, C 1 -C 4 straight or branched chain alkyl, 4-pyridyl, benzyl and phenyl, said R having one to three substituent(s) selected from the group consisting of hydrogen, 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 and Ar.
36 . The method of claim 35 , wherein said compound is selected from the group consisting of:
2-[[(N-hydroxy)carboxamido]methyl]pentanedioic acid;
2-[[N-hydroxy(methyl)carboxamido]methyl]pentanedioic acid;
2-[[N-hydroxy(benzyl)carboxamido]methyl]pentanedioic acid;
2-[[N-hydroxy(phenyl)carboxamido]methyl]pentanedioic acid;
2-[(N-hydroxy(2-phenylethyl)carboxamido]methyl]pentanedioic acid;
2-[[N-hydroxy(ethyl)carboxamido]methyl]pentanedioic acid;
2-[[N-hydroxy(propyl)carboxamido]methyl]pentanedioic acid;
2-[[N-hydroxy (3-phenylpropyl)carboxamido]methyl]pentanedioic acid; and
2-[[N-hydroxy(4-pyridyl)carboxamido]methyl]pentanedioic acid.
37 . The method of claim 29 , wherein said glutamate abnormality is selected from the group consisting of epilepsy, stroke, Alzheimer's disease, Parkinson's Disease, Amyotrophic Lateral Sclerosis (ALS), Huntington's Disease, schizophrenia, chronic pain, ischemia and neuronal insult.
38 . The method of claim 37 , wherein said glutamate abnormality is ischemia.
39 . A method of treating a prostate disease in an animal, comprising administering an effective amount of the compound of claim 1 to said animal.
40 . The method of claim 39 , wherein in said compound, Y is CH 2 .
41 . The method of claim 40 , wherein in said compound, X is
42 . The method of claim 41 , wherein in said compound, R is selected from the group consisting of hydrogen, C 1 -C 4 straight or branched chain alkyl, 4-pyridyl, benzyl and phenyl, said R having one to three substituent(s) selected from the group consisting of hydrogen, C 3 -C 3 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 and Ar.
43 . The method of claim 42 , wherein said compound is selected from the group consisting of:
2-[[(N-hydroxy)carbamoyl]methyl]pentanedioic acid;
2-[[(N-hydroxy-N-methyl)carbamoyl]methyl]pentanedioic acid;
2-[[(N-butyl-N-hydroxy)carbamoyl]methyl]pentanedioic acid;
2-[[(N-benzyl-N-hydroxy)carbamoyl]methyl]pentanedioic acid;
2-[[(N-hydroxy-N-phenyl)carbamoyl]methyl]pentanedioic acid;
2-[[(N-hydroxy-N-2-phenylethyl)carbamoyl]methyl]pentanedioic acid;
2-[[(N-ethyl-N-hydroxy)carbamoyl]methyl]pentanedioic acid;
2-[[(N-hydroxy-N-propyl)carbamoyl]methyl]pentanedioic acid;
2-[[(N-hydroxy-N-3-phenylpropyl)carbamoyl]methyl]pentanedioic acid; and
2-[(N-hydroxy-N-4-pyridyl)carbamoyl]methyl]pentanedioic acid.
44 . The method of claim 40 , wherein in said compound, X is
45 . The method of claim 44 , wherein in said compound, R is selected from the group consisting of hydrogen, C 1 -C 4 straight or branched chain alkyl, 4-pyridyl, benzyl and phenyl, said R having one to three substituent(s) selected from the group consisting of hydrogen, 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 and Ar.
46 . The method of claim 45 , wherein said compound is selected from the group consisting of:
2-[[(N-hydroxy)carboxamido]methyl]pentanedioic acid;
2-[[N-hydroxy(methyl)carboxamido]methyl]pentanedioic acid;
2-[[N-hydroxy(benzyl)carboxamidolmethyl]pentanedioic acid;
2[[N-hydroxy(phenyl)carboxamido]methyl]pentanedioic acid;
2-[(N-hydroxy(2-phenylethyl)carboxamido]methyl]pentanedioic acid;
2-[[N-hydroxy(ethyl)carboxamido]methyl]pentanedioic acid;
2-[[N-hydroxy(propyl)carboxamido]methyl]pentanedioic acid;
2-[[N-hydroxy (3-phenylpropyl)carboxamido]methyl]pentanedioic acid; and
2-[[N-hydroxy(4-pyridyl)carboxamido]methyl]pentanedioic acid.
47 . The method of claim 39 , wherein said prostate disease is prostate cancer or benign prostatic hyperplasia.Join the waitlist — get patent alerts
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