1,2-Dioxetane derivatives and reagents employing them

Details 1,2-Dioxetane derivatives and reagents employing them 1,2-Dioxetane derivatives and reagents employing them

2003-03-07

2004-06-08

McKane, Joseph K. (Department: 1626)

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

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

C549S050000

Reexamination Certificate

active

06747160

ABSTRACT:

The present invention relates to 1,2-dioxetane derivatives. The 1,2-dioxetane derivatives of the present invention are compounds which are capable of inducing chemiluminescence and can be used, for example, as substrates for immunoassay.
Heretofore, various 1,2-dioxetane derivatives have been synthesized, and it is known that compounds having a spiroadamantyl group bonded at the 3-position, are useful as chemiluminescent substrates (see, for example, JP-B-5-21918, and JP-B-5-45590). Further, as produced by the present inventors, various compounds are known (see, for example, JP-A-8-245615, JP-A-8-169885, JP-A-8-165287 and JP-A-2002-338576). These 1,2-dioxetane derivatives have an enzyme recognition site such as a phosphate ester group and will be triggered by an enzyme to produce luminescence. A series of such compounds are useful for a method wherein the activities of an enzyme labeled on an antigen or antibody adsorbed on a solid phase after an immunoreaction, are detected by a chemiluminescent reaction. In such a method, a 1,2-dioxetane solution is added to the measuring system, whereby even in a case no enzyme is present, luminescence by a heat or by a non-enzymatic decomposition reaction of e.g. a trace amount of impurities, will be detected, which leads to a rise of the background. Such a rise of the background is substantially influential to the detection sensitivity and thus is problematic.
Therefore, various compounds have been synthesized (see, for example, Japanese Patent 2,572,171, JP-A-08-502968 and JP-A-2002-508654), but the low stability of such dioxetane compounds themselves has still remained as a problem to be solved.
As mentioned above, various studies have been made with respect to 1,2-dioxetane derivatives, and various compounds have been produced. However, for such compounds to be useful in the fields of e.g. clinical tests, the compounds themselves are required to be stable and easy to handle and to have a performance to provide a low background for measurement to present high sensitivity. Accordingly, it has been desired to develop a compound superior to conventional compounds.
Under these circumstances, the present inventors have conducted an extensive study to develop a compound which is superior to conventional compounds and as a result, have succeeded in synthesizing a 1,2-dioxetane derivative which has a stable structure and is able to reduce the background for the measurement by e.g. an immunoassay and which can be labeled to an organic compound or a biological molecule. The present invention has been accomplished on the basis of this discovery.
Namely, the present invention provides a 1,2-dioxetane derivative of the formula (I):
wherein Ar is an aryl group which may have an alkyl group, an aryl group, a halogen atom, an alkoxyl group, a carboxyl group, a formyl group, an alkyl ester, an aryl ester, an alkylketone, an arylketone or a hetero ring bonded thereto, X is a substituent capable of labeling an organic compound or a biological molecule, or an ester, Y is a hydrogen atom, an acyl group or a group of the formula —Si(R
4
R
5
R
6
) (wherein each of R
4
, R
5
and R
6
which are independent of one another, is an alkyl group or an aryl group), Z is an alkyl group, an aryl group, an oxygen atom, a sulfur atom, a carbonyl group, —(CO)—O—, —O—(CO)—, —NH—, —NH—CO—, —CO—NH—, —OSi(R
7
R
8
)— (wherein each of R
7
and R
8
which are independent of each other, is an alkyl group or aryl group) or a group of the formula —(R
9
R
10
)SiO— (wherein each of R
9
and R
10
which are independent of each other, is an alkyl group or an aryl group), each of R
1
and R
2
is an alkyl group or an aryl group, and R
3
is a spacer.
Further, the present invention provides a 1,2-dioxetane derivative of the formula (III):
wherein Ar is an aryl group which may have an alkyl group, an aryl group, a halogen atom, an alkoxyl group, a carboxyl group, a formyl group, an alkyl ester, an aryl ester, an alkylketone, an arylketone or a hetero ring bonded thereto, X is a substituent capable of labeling an organic compound or a biological molecule, or an ester, V is a carbonyl group or a group of the formula —Si(R
15
R
16
)— (wherein each of R
15
and R
16
which are independent of each other, is an alkyl group or aryl group), each of R
11
and R
12
which are independent of each other, is a hydrogen atom, an alkyl group or an aryl group, or R
11
and R
12
may together form a cyclic or polycyclic organic ring group spiro-bonded to the dioxetane ring, R
13
is an alkyl group or an aryl group, or R
13
and R
11
, or R
13
and R
12
, may together form a condensed ring containing the dioxetane ring and a hetero atom, and R
14
is a spacer.
Still further, the present invention provides a chemiluminescent reagent which contains the above 1,2-dioxetane derivative. Still further, the present invention provides an immunoassay reagent wherein the above 1,2-dioxetane derivative is bonded to a substance having a specific affinity via a part of its X or W.


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