Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
1997-11-28
2001-09-04
Owens, Amelia (Department: 1625)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
active
06284899
ABSTRACT:
BACKGROUND OF THE INVENTION
(1) Field of the Invention
The present invention relates to chemiluminescent 1,2-dioxetane compounds that can be triggered by reagents including enzymes and other chemicals to generate light. In particular, the present invention relates to stable aryl group-substituted 1,2-dioxetanes that contain a triggerable X-oxy group (OX) which is a substituent of the aryl group, in which the stable 1,2-dioxetane forms an unstable dioxetane compound by removal of X, which decomposes to produce light and two carbonyl compounds.
(2) Description of Related Art
a. Preparation of 1,2-Dioxetanes. Kopecky and Mumford reported the first synthesis of a dioxetane (3,3,4-tri-methyl-1,2-dioxetane by the base-catalyzed cyclization of a &bgr;-bromohydroperoxide, which, in turn, is prepared from the corresponding alkene (K. R. Kopecky and C. Mumford,
Can. J. Chem.,
47, 709 (1969)). Although this method has been used to produce a variety of alkyl and aryl-substituted 1,2-dioxetanes, it can not be used for the preparation of dioxetanes derived from vinyl ethers, vinyl sulfides and enamines.
An alternate synthetic route to 1,2-dioxetanes, especially those derived from vinyl ethers, vinyl sulfides and enamines was independently reported by Bartlett and Schaap (P. D. Bartlett and A. P. Schaap,
J. Am. Chem. Soc.,
92, 3223 (1970)) and Mazur and Foote (S. Mazur and C. S. Foote,
J. Am. Chem. Soc.,
92, 3225 (1970)). Photochemical addition of a molecule of oxygen to the appropriate alkene compound in the presence of a photosensitizer produces 1,2-dioxetanes in high yield. This method has been used to produce a large number of dioxetane compounds (K. R. Kopecky in
Chemical and Biological Generation of Excited States,
W. Adam and G. Cilento, (Eds.), Academic Press, New York, p. 85, 1982).
Two limitations of this method have been reported. Certain alkenes with aromatic substituents were found to produce six membered ring peroxides known as endoperoxides on photooxygenation (A. P. Schaap, P. A. Burns and K. A. Zaklika,
J. Am. Chem. Soc.,
99, 1270 (1977)). Alkenes with reactive allylic hydrogens frequently undergo an alternate reaction, the “ene” reaction, producing an allylic hydroperoxide instead of a dioxetane (A. Baumstark in Advances In Oxygenated Processes, JAI Press, Greenwich, Conn., 1988; Vol.1, pp 31-84).
b. Thermally Stable Dioxetanes from Sterically Hindered Alkenes. The dioxetane derived from the hindered alkene adamantylideneadamantane which was discovered by Wynberg (J. H. Wieringa, J. Strating, H. Wynberg and W. Adam,
Tetrahedron Lett.,
169 (1972) was shown to have an activation energy for decomposition of 37 kcal/mol and a half life (t
½
) at 25° C. of several years (N. J. Turro, G. Schuster, H. C. Steinmetzer, G. R. Faler and A. P. Schaap,
J. Amer. Chem. Soc.,
97, 7110 (1975)). Others have shown that a spiro-fused polycyclic group such as the adamantyl group can help to increase the stability of dioxetanes derived from amino-substituted alkenes (F. McCapra, I. Beheshti, A. Burford, R. A. Hann and K. A. Zaklika,
J. Chem. Soc., Chem. Comm.,
944 (1977)), vinyl ethers (W. Adam, L. A. Encarnacion and K. zinner,
Chem. Ber.,
116, 839 (1983)) and vinyl sulfides (G. G. Geller, C. S. Foote and D. B. Pechman,
Tetrahedron Lett.,
673 (1983); W. Adam, L. A. Arias and D. Schuetzow,
Tetrahedron Lett.,
2835 (1982)) which would be unstable without this group.
c. Chemical Triggering of Dioxetanes. The first example in the literature is described in relation to the hydroxy-substituted dioxetane derived from the 2,3-diaryl-1,4-dioxene (A. P. Schaap and S. Gagnon,
J. Amer. Chem. Soc.,
104, 3504 (1982)). However, the hydroxy-substituted dioxetane and any other examples of the dioxetanes derived from the diaryl-1,4-dioxenes are relatively unstable having half-lives at 25° C. of only a few hours. Further, these non-stabilized dioxetanes are destroyed by small quantities of amines (T. Wilson,
Int. Rev. Sci.: Chem., Ser. Two,
9, 265 (1976)) and metal ions (T. Wilson, M. E. Landis, A. L. Baumstark, and P. D. Bartlett,
J. Amer. Chem. Soc.,
95, 4765 (1973); P. D. Bartlett, A. L. Baumstark, and M. E. Landis,
J. Amer. Chem. Soc.,
96, 5557 (1974)), both components used in the aqueous buffers for biological assays.
Examples of the chemical triggering of adamantyl-stabilized dioxetanes were first reported in U.S. patent application (A. P. Schaap, patent application Ser. No. 887,139, filed Jul. 17, 1986) and a paper (A. P. Schaap, T. S. Chen, R. S. Handley, R. DeSilva, and B. P. Giri,
Tetrahedron Lett.,
1155 (1987)). These dioxetanes exhibit thermal half-lives of years but can be triggered to produce efficient chemiluminescence on demand. Moderately stable benzofuranyl dioxetanes substituted with trialkylsilyl and acetyl-protected phenolic groups which produce weak chemiluminescence have also been reported (W. Adam, R. Fell, M. H. Schulz,
Tetrahedron,
49(11), 2227-38 (1993); W. Adam, M. H. Schulz,
Chem. Ber.,
125, 2455-61 (1992)). The stabilizing effect of other rigid polycyclic groups has also been reported (P. D. Bartlett and M. Ho,
J. Am. Chem. Soc.,
96, 627 (1975); P. Lechtken,
Chem. Ber.,
109, 2862 (1976)). A PCT application, WO 94/10258 discloses chemical triggering of dioxetanes bearing various rigid polycyclic substituents.
d. Enzymatic Triggering of Adamantyl Dioxetanes. Dioxetanes which can be triggered by an enzyme to undergo chemiluminescent decomposition are disclosed in U.S. patent application (A. P. Schaap, patent application Ser. No. 887,139) and a series of papers (A. P. Schaap, R. S. Handley, and B. P. Giri,
Tetrahedron Lett.,
935 (1987); A. P. Schaap, M. D. Sandison, and R. S. Handley,
Tetrahedron Lett.,
1159 (1987) and A. P. Schaap,
Photochem. Photobiol.,
47S, 50S (1988)). The highly stable adamantyl-substituted dioxetanes bearing a protected aryloxide substituent are triggered to decompose with emission of light by the action of an enzyme in an aqueous buffer to give a strongly electron-donating aryloxide anion which dramatically increases the rate of decomposition of the dioxetane. As a result, chemiluminescence is emitted at intensities several orders of magnitude above that resulting from slow thermal decomposition of the protected form of the dioxetane. U.S. Pat. No. 5,068,339 to Schaap discloses enzymatically triggerable dioxetanes with covalently linked fluorescer groups. Decomposition of these dioxetanes results in enhanced and red-shifted chemiluminescence through intramolecular energy transfer to the fluorescer. U.S. Pat. No. 4,952,707 to Edwards discloses enzymatically triggerable dioxetanes bearing an adamantyl group and 2,5- or 2,7-disubstituted naphthyl groups. U.S. Pat. Nos. 5,112,960, 5,220,005, 5,326,882 and a PCT application (88 00695) to Bronstein disclose triggerable dioxetanes bearing adamantyl groups substituted with various groups including chlorine, bromine carboxyl, hydroxyl, methoxy and methylene groups. A publication (M. Ryan, J. C. Huang, O. H. Griffith, J. F. Keana, J. J. Volwerk,
Anal. Biochem.,
214(2), 548-56 (1993)) discloses a phosphodiester-substituted dioxetane which is triggered by the enzyme phospholipase. U.S. Pat. No. 5,132,204 to Urdea discloses dioxetanes which require two different enzymes to sequentially remove two linked protecting groups in order to trigger the chemiluminescent decomposition. U.S. Pat. No. 5,248,618 to Haces discloses dioxetanes which are enzymatically or chemically triggered to unmask a first protecting group generating an intermediate which spontaneously undergoes an intramolecular reaction to split off a second protecting group in order to trigger the chemiluminescent decomposition.
e. Enhanced Chemiluminescence from Dioxetanes in the Presence of Surfactants. Enhancement of chemiluminescence from the enzyme-triggered decomposition of a stable 1,2-dioxetane in the presence of water-soluble substances including an ammonium surfactant and a fluorescer has been reported (A. P. Schaap, H. Akhavan and L. J. Romano, Clin. Chem., 35(9), 1863 (1989)). Fluorescent micelles consist
Akhavan-Tafti Hashem
Schaap Arthur Paul
Handley Richard S.
Owens Amelia
The Board of Governors of Wayne State University
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