US 5,516,647 A · Compounds useful as alkaline phosphatase inhibitors and therapeutic agents

Abstract

The present invention discloses novel compounds useful as alkaline phosphatase inhibitors and therapeutic agents. Preferably, the novel compounds are useful as selective inhibitors of human alkaline phosphatases as opposed to Escherichia coli alkaline phosphatases. The novel compounds can also be used as cancer therapeutic agents, anti-depressive agents, anti-anergic agents, and antihelminthic agents. The novel compounds have the following general formula: ##STR1## wherein R' is an aryl, aryl ether, aryl thioether, aromatic heterocyclic, aromatic heterocyclic thioether, or aromatic heterocyclic ether group. More preferably, R' is a phenyl or a pyridine. Most preferably, R' is of the following formula: ##STR2## 2-thiopyridine, or ##STR3## 2-oxypyridine. R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.1 ', R.sub.2 ', R.sub.3 ', R.sub.4 ', and R.sub.5 ' can be the same or different, and at least one of which is selected from the group consisting of: H, C.sub.1 -C.sub.6 alkyl, halo C.sub.1 -C.sub.6 alkyl, phenyl, C.sub.1 -C.sub.6 alkoxy, phenoxy, trifluoromethyl, nitro, amino, carboxy, and halo groups with the proviso that each novel compound has no more than three substituents. Hydrogen is not considered a substituent.

Claims34

Dependent claims

A compound selected from the group consisting of;

General Formula 1, General Formula 2, and a salt of General Formula 1 or 2;
wherein General Formulae 1 and 2 are as follow:
##STR10## wherein:
R' is selected from the group consisting of:
aryl, aryl ether, aryl thioether, aromatic heterocyclic, aromatic heterocyclic thioether, and aromatic heterocyclic ether groups;
R.sub.1, R.sub.2, R.sub.3 and R.sub.4 are the same or different wherein R.sub.1, R.sub.2, R.sub.3 and R.sub.4 are selected from the group consisting of H, C.sub.1 -C.sub.6 alkyl, halo C.sub.1 -C.sub.6 alkyl, phenyl, C.sub.1 -C.sub.6 alkoxy, phenoxy, trifluoromethyl, nitro, amino, carboxy, and halo groups, with the proviso that the compound has no more than three substituents;
and
R', R.sub.1, R.sub.2, R.sub.3 and R.sub.4 do not significantly prevent the compound from binding to and inhibiting the enzymatic activity of alkaline phosphatase.

5 more elements

An assay for an analyte in a sample, wherein the sample is believed likely to contain mammalian alkaline phosphatase, comprising the steps of:

a) exposing the sample to a solid support capable of binding the analyte and mammalian alkaline phosphatase;
b) incubating the sample and the solid support for a time sufficient for the binding of the analyte to the solid support;
c) removing reagents which are not bound to the solid support;
d) exposing the solid support to a reagent capable of binding to the analyte, the reagent being labeled with non-mammalian alkaline phosphatase;
e) incubating the solid support and the reagent for a time sufficient for the binding of the reagent to the analyte which is bound to the solid support;
f) removing the reagent which is not bound to the solid support bound analyte;
g) adding a compound and a substrate for alkaline phosphatase to the solid support;
and
h) assaying for the presence of the analyte by assaying for the conversion of the substrate into an enzymatic product of the non-mammalian alkaline phosphatase;
wherein the compound has the formula selected from the group consisting of General Formula 1, General Formula 2, and a salt of General Formulae 1 and 2;
wherein General Formulae 1 and 2 are as follow:
##STR14## wherein:
R' is selected from the group consisting of:
aryl, aryl ether, aryl thioether, aromatic heterocyclic, aromatic heterocyclic thioether, and aromatic heterocyclic ether groups;
R.sub.1, R.sub.2, R.sub.3 and R.sub.4 are the same or different wherein R.sub.1, R.sub.2, R.sub.3 and R.sub.4 are selected from the group consisting of H, C.sub.1 -C.sub.6 alkyl, halo C.sub.1 -C.sub.6 alkyl, phenyl, C.sub.1 -C.sub.6 alkoxy, phenoxy, trifluoromethyl, nitro, amino, carboxy, and halo groups, with the proviso that the compound has no more than three substituents;
and
R', R.sub.1, R.sub.2, R.sub.3 and R.sub.4 do not significantly prevent the novel compound from binding to and inhibiting the enzymatic activity of mammalian alkaline phosphatase more than inhibiting the enzymatic activity of non-mammalian alkaline phosphatase.

14 more elements

A method for determining the presence or amount of an analyte in a test sample, wherein the test sample may contain mammalian alkaline phosphatase, comprising the steps of:

a) sequentially or simultaneously allowing the test sample, a binding molecule of the analyte, a non-mammalian alkaline phosphatase, alkaline phosphatase substrate, and a compound to come into contact;
and
b) monitoring changes in the rate of catalysis of the alkaline phosphatase substrate by the non-mammalian alkaline phosphatase, the changes being dependent upon the analyte present in the reaction mixture;
wherein:
the non-mammalian alkaline phosphatase and the analyte compete for binding to the binding molecule;
the enzymatic activity of the non-mammalian alkaline phosphatase is when it is bound to the binding molecule,
the compound has a formula selected from the group consisting of:
General Formula 1, General Formula 2, and a salt of General Formulae 1 and 2;
wherein General Formulae 1 and 2 are as follow:
##STR15## wherein:
R' is selected from the group consisting of:
aryl, aryl ether, aryl thioether, aromatic heterocyclic, aromatic heterocyclic thioether, and aromatic heterocyclic ether groups;
R.sub.1, R.sub.2, R.sub.3 and R.sub.4 are the same or different wherein R.sub.1, R.sub.2, R.sub.3 and R.sub.4 are selected from the group consisting of H, C.sub.1 -C.sub.6 alkyl, halo C.sub.1 -C.sub.6 alkyl, phenyl, C.sub.1 -C.sub.6 alkoxy, phenoxy, trifluoromethyl, nitro, amino, carboxy, and halo groups, with the proviso that the compound has no ore than three substituents;
and
R', R.sub.1, R.sub.2, R.sub.3 and R.sub.4 do not significantly prevent the compound from binding to and inhibiting the enzymatic activity of mammalian alkaline phosphatase more than inhibiting the enzymatic activity of non-mammalian alkaline phosphatase.

12 more elements

Dependencies are inferred from the claim text.

Compounds useful as alkaline phosphatase inhibitors and therapeutic agents

Life of this patent

Compounds useful as alkaline phosphatase inhibitors and therapeutic agents

Life of this patent

Abstract

Claims34