WO1992009580A1 - Composes chimioluminescents - Google Patents

Composes chimioluminescents Download PDF

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Publication number
WO1992009580A1
WO1992009580A1 PCT/US1991/006861 US9106861W WO9209580A1 WO 1992009580 A1 WO1992009580 A1 WO 1992009580A1 US 9106861 W US9106861 W US 9106861W WO 9209580 A1 WO9209580 A1 WO 9209580A1
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Prior art keywords
group
chemiluminescent
salt
groups
moiety
Prior art date
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PCT/US1991/006861
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English (en)
Inventor
M. Parameswara Reddy
Maged Aziz Michael
Chan S. Oh
Thomas S. Dobashi
Nabih S. Girgis
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Beckman Instruments, Inc.
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Priority to JP1992600006U priority Critical patent/JPH05500010U/ja
Publication of WO1992009580A1 publication Critical patent/WO1992009580A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D219/00—Heterocyclic compounds containing acridine or hydrogenated acridine ring systems
    • C07D219/04—Heterocyclic compounds containing acridine or hydrogenated acridine ring systems with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the ring system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D221/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00
    • C07D221/02—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00 condensed with carbocyclic rings or ring systems
    • C07D221/04—Ortho- or peri-condensed ring systems
    • C07D221/06—Ring systems of three rings
    • C07D221/10—Aza-phenanthrenes
    • C07D221/12—Phenanthridines
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/56—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
    • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/553—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having one nitrogen atom as the only ring hetero atom
    • C07F9/576—Six-membered rings
    • C07F9/64—Acridine or hydrogenated acridine ring systems
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/58—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving labelled substances
    • G01N33/582—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving labelled substances with fluorescent label

Definitions

  • the present invention is directed to chemiluminescent compounds for use as labels in analytic reactions such as immunochemical reactions.
  • radioactive labels fluorescent labels, and enzyme labels. While all of these labels are used extensively, each type of label has unique disadvantages.
  • Radioactive labels particularly high-energy radioactive labels such as 125 I (the most commonly employed radioisotope in immunochemistry), have several disadvantages.
  • the radioisotopes have a short half-life, i.e., 125 I decays with a half-life of approximately sixty days.
  • 125 I the radioactive atom incorporated in a molecule decays, it destroys the molecule in which it is incorporated and can cause damage to other molecules in the preparation.
  • radioactively labeled preparations have extremely short shelf-lives. Moreover, because of the radiation they emit, radioactive labels require special safety
  • Fluorescent labels avoid the disadvantages of radioactive labels but have other disadvantages of their own. Notably, they are less sensitive than radioactive labels, and the use thereof requires activation by an extrinsic light source. This requirement of activation by an extrinsic light source makes their detection more difficult, as two wavelengths of light are involved, an emission wavelength and an excitation wavelength.
  • Enzyme labels can be extremely sensitive, but these too have disadvantages. Their detection requires at least one additional step, a development step, to allow the enzyme to carry out its reaction so that a detectable product can be produced. This step requires the use of additional reagents to the reaction, including buffers, substrates and/or coenzymes. Moreover, it is not possible to use enzyme labels in all assays. If the assay requires a step that inactivates or denatures the enzyme or results in ionic, pH, or other conditions incompatible with the activity of the particular enzyme used as the label, enzyme labels cannot be used. Because of the above deficiencies, increased attenti.on has focused on chemilumi.nescent labels as alternative labels for these types of assays.
  • Chemiluminescence is a direct generation of light from a chemical reaction. The mechanism of most
  • chemiluminescent reactions is not known in detail, but a generalized mechanism can be outlined:
  • Compound A undergoes a chemical reaction, usually oxidation, to yield a product in an electronically excited state ("B * "). As this product returns to its ground state (“B”), it gives off energy in the form of light ( “hv” ). Typically, the light is in the visible range.
  • chemiluminescence occurs when the vibronically excited product of an exogenic chemical reaction reverts to its ground state with the emission of protons, with the reactions invariably being both oxidative and biphasic. Because the excitation energy is obtained from the chemical energy of reaction, the process is chemiluminescence.
  • the characteristics and behavior of several different chemiluminescent compounds can be found in Gundermann & McCapra,
  • Chemiluminescent labels are preferred over the previously noted labels for several reasons.
  • Chemiluminescent labels have high sensitivity ⁇ in many cases, sensitivity down to the femtomole (10 -15 mole) to attomole (10 -18 mole) range has been recorded.
  • chemiluminescent labels can thus match or exceed the sensitivity of radioactive labels or enzyme labels.
  • Luminol and isoluminol derivatives are the most widely used chemiluminescent reagents for immunoassays.
  • the light-yielding reaction is initiated by oxidation with alkaline hydrogen peroxide in the presence of catalysts such as horseradish peroxidase,
  • AEEI Aminobutylethyl isoluminol
  • a second group of chemiluminescent reagents is aryl oxalates. These reagents have been used as
  • 10-methyl-acridinium-9-carboxylic acid aryl esters are chemiluminescent in the presence of alkaline hydrogen peroxide and in the absence of a catalyst.
  • the mechanism is believed to involve initial attack by a hydroperoxide anion, followed by intramolecular displacement of the phenolate (the "leaving group") to give a strained dioxetane-one.
  • the strained dioxetane-one decomposes to CO 2 and excited N-methyl-acridone, which emits light at 430 nm.
  • Carboxy-substituted acridinium salts have been used as labels in immunoassays.
  • 5-methyl-phenanthridinium-6-carboxylic acid aryl esters which are isomeric with the acridinium aryl esters, have been used as labels in immunoassays.
  • chemiluminescent labels have several disadvantages, including relatively low quantum yield and undue sensitivity to hydrolysis, especially under conditions necessary to preserve the stability of the labile biological molecules such as antibodies to which they are attached. For example, it has been reported that antibody-conjugated phenyl
  • 10-methyl-9-acridinium carboxylates lose More than 10% of their activity within three days at about pH 4.0. These labels are only stable below pH 4.0, a degree of acidity to which many antibodies and other proteins are
  • chemiluminescent labels due to the disadvantages of radioactive, fluorescent, and enzyme labels, acridinium, phenanthridinium, or other chemiluminescent compounds useable under conditions compatible with labeling of biological molecules would be useful and highly
  • U represents a chemical group that can produce light by chemiluminescence
  • F represents a leaving group
  • n has a value of at least one.
  • One class of these chemiluminescent compounds comprises salts in which the leaving group contains a carboxyl carbon atom or its isoelectronic equivalent and a five-membered unsaturated ring, including at least one heteroatom.
  • This class of molecules comprises a cation and an anion wherein:
  • n is at least one
  • a + is a positively charged moiety capable of producing light by chemiluminescence, such as an acridinium, substituted acridinium, phenanthridinium, substituted phenanthridinium, quinolinium, substituted quinolinium, benzacridinium, or substituted
  • R' is C 1 -C 5 alkyl
  • W is selected from the group consisting of hydrogen and C 1 -C 5 alkyl
  • X is selected from the group consisting of O, S, Se, Te and NR" where R" is C 1 -C 5 alkyl or arylsulfonyl;
  • Q is selected from the group consisting of the following structures: an d
  • a 2 , A 3 and A 4 are each independently selected from the group consisting of a valence bond, C 1 -C 10 alkyl, C 2 -C 10 alkenyl, C 2 -C 10 alkynyl, C 3 -C 12 cycloalkyl, C 5 -C 12 cycloalkenyl and aryl; and
  • (C) Z 2 , Z 3 and Z 4 are each independently selected from the group consisting of hydrogen, carboxyl, carboxyl halide, sulfonyl halide, carboalkoxy, carboxyl acylate, carboxamido, cyano, carboxime, isocyanate, sulfo, N-succinimidylcarboxyl and N-maleimido, except that where all of A 2 , A 3 , and A 4 are valence bonds, all of Z 2 , Z 3 , and Z 4 are not hydrogen unless X is NR" where R" is arylsulfonyl; and
  • a + can be an acridinium moiety represented by the following schematic:
  • a 1 is selected from the group consisting of a valence bond, C 1 -C 10 alkyl, C 2 -C 10 alkenyl, C 2 -C 10 alkynyl, C 3 -C 12 cycloalkyl, C 5 -C 12 cycloalkenyl, and aryl;
  • Z 1 is selected from the group consisting of hydrogen, methyl, carboxyl, carboxyl halide, sulfonyl halide, carboalkoxy, carboxyl acylate, carboxamido, cyano, carboxime, isocyanato, sulfo, N-succinimidylcarboxyl, and N-maleimido groups, with the condition that where A 1 is a valence bond, Z 1 is not hydrogen;
  • R 1 , R 3 , R 5 , R 7 and R 9 are each independently selected from the group consisting of a valence bond, hydrogen, and a moiety A-Z where A is defined as A 1 above and Z is defined as Z 1 above, with the conditions that only one of R 1 , R 3 , R 5 , R 7 and R 9 is a valence bond; and
  • R 2 , R 4 , R 6 and R 8 are each independently selected from the group consisting of hydrogen and a moiety A-Z where A is defined as A 1 above and Z is defined as Z 1 above.
  • A is defined as A 1 above
  • Z is defined as Z 1 above.
  • at least one of the carbon atoms of A 1 other than the carbon atom located furthest from the acridinium moiety can be substituted with a substituent selected from the group consisting of hydroxy, halo, alkoxy, amino, alkylamino, arylamino, carboxyl, carboxyester, carboxythioester,
  • sulfoester sulfinyl, cyano, isothiocyano, ureido, oxo, imino, mercapto, carboxamide, alkylthio, mercaptoester, phosphoryl, and phosphorylester.
  • a 1 is selected from the group consisting of substituted and unsubstituted straight chain aliphatic groups
  • at least one of the carbon atoms of A 1 other than the carbon atom located furthest from the acridinium moiety can be replaced with a replacement moiety selected from the group consisting of -O-, -NH-, and -NL-, wherein L is selected from the group consisting of alkyl groups, cycloalkyl groups, oxo groups, hydroxy groups, sulfo groups, sulfoester groups, carboxyester groups,
  • a 1 can be a valence bond, in which case Z 1 can be selected from the group consisting of carboxyl, carboxyl halide, sulfonyl halide, carboalkoxy, carboxyl acylate, carboxamido, cyano, carboxime, isocyanato, sulfo, N-succinimidylcarboxyl, and N-maleimido.
  • These reactive groups can be used to couple the chemiluminescent compound to a biomolecule.
  • R 5 is a valence bond and the leaving group moiety is linked to R 5 ;
  • R 1 , R 2 , R 3 , R 4 , R 6 , R 7 , R 8 , and R 9 are each hydrogen.
  • Z' is O and X is S.
  • Q is
  • Y is S.
  • a 1 is a valence bond and Z 1 is CH 3 ;
  • a 2 , A 3 and A 4 are each valence bonds; and the anion is CF 3 SO 3 .
  • the moiety A + can also be a phenanthridinium moiety represented by the structure
  • a 1 is selected from the group consisting of a valence bond, C 1 -C 10 alkyl, C 2 -C 10 alkenyl, C 2 -C 10 alkynyl, C 3 -C 12 cycloalkyl, C 5 -C 12 cycloalkenyl, and aryl;
  • Z 1 is selected from the group consisting of hydrogen, methyl, carboxyl, carboxyl halide, sulfonyl halide, carboalkoxy, carboxyl acylate, carboxamido, cyano, carboxime, isocyanato, sulfo, N- succinimidylcarboxyl, and N-maleimido groups, except that where A 1 is a valence bond, Z 1 is not hydrogen;
  • each of R 14 , R 17 , and R 18 is selected from the group consisting of a valence bond, hydrogen, and a moiety A-Z in which A is one of the groups defined as A 1 above and in which Z is one of the groups defined as Z 1 above, in which the A and Z can be selected independently for each of R 14 , R 17 , and R 18 with the condition that only one of R 14 , R 17 , and R 18 is a valence bond; and
  • each of R 10 , R 11 , R 12 , R 13 , R 15 , and R 16 is selected from the group consisting of hydrogen and the moiety A-Z, in which the A and Z can be selected
  • R 10 , R 11 , R 12 , R 13 , R 15 , and R 16 independently for each of R 10 , R 11 , R 12 , R 13 , R 15 , and R 16 .
  • the phenanthridinium moiety can be substituted in a manner analogous to that for the acridinium moiety previously described.
  • a second ring of at least five atoms can be formed in the moiety Q by
  • Q is selected from the group
  • a 2 , A 3 , or A 4 not involved in formation of the second ring is selected from the group consisting of a valence bond, C 1 -C 10 alkyl, C 2 -C 10 alkenyl, C 2 -C 10 alkynyl, C 3 -C 12 cycloalkyl, C 5 -C 12
  • the moiety Z 2 , Z 3 , or Z 4 not involved in the formation of the second ring is selected from the group consisting of hydrogen, carboxyl, carboxyl halide, sulfonyl halide, carboalkoxy, carboxyl acylate.
  • a + is a positively charged moiety capable of producing light by chemiluminescence
  • R' is selected from the group consisting of hydrogen and C 1 -C 5 alkyl
  • chemiluminescence can be selected from the group
  • chemiluminescent compounds Another class of chemiluminescent compounds according to the present invention is chemiluminescent
  • salts comprising an anion and a cation, the cation
  • the chemical group that can produce light by chemiluminescence is a heterocyclic ring or ring system selected from the group consisting of acridinium, phenanthridinium, quinolinium, and benzacridinium;
  • R 1 is selected from the group consisting of alkoxy groups, aryloxy groups, thioderivatives of alkoxy groups, thioderivatives of aryloxy groups, pyrrole and substituted derivatives thereof, imidazole and
  • substituted derivatives thereof pyrazole and substituted derivatives thereof, triazole and substituted derivatives thereof, oxazole and substituted derivatives thereof, thiazole and substituted derivatives thereof, tetrazole and substituted derivatives thereof, indole and
  • R 2 is selected from the group consisting of hydrogen, alkyl groups and thioderivatives thereof, aryl groups and thioderivatives thereof, alkoxy groups and thioderivatives thereof, aryloxy groups and
  • R 3 is selected from the group consisting of O, S, NH, NR 1 , NR 2 , CH 2 , C (R 1 ) 2 , C(R 2 ) 2 , and CR 1 R 2 where R 1 and R 2 are as defined above;
  • the anion is selected from the group consisting of sulfate, methosulfate, perhalomethosulfate, haloborate, haloacetate, halophosphate, phosphate, halide, phosphite, nitrate, nitrite, carbonate, and bicarbonate.
  • the chemical group producing light is preferably N-methylacridinium, and the leaving group is preferably
  • R 1 is selected from the group consisting of pyrrole, pyrazole, 2-methylindole, and isatin and R 3 is O.
  • Another aspect of the present invention is a method for determining the quantity of a biomolecule in solution by using any of the chemiluminescent compounds of ; the present invention.
  • the method comprises:
  • these chemiluminescent compounds comprise a conjugated heterocyclic ring or ring system covalently linked to a stable leaving group.
  • the present invention encompasses both a number of possible conjugated heterocyclic rings or ring systems and a number of different leaving groups.
  • the leaving groups all include a polar moiety containing phosphorus, sulfur, or carbon bonded to a different atom, which can be carbon, nitrogen, oxygen, or sulfur. This bond can be a double bond.
  • the leaving group can include a carbonyl, thiocarbonyl, sulfone, sulfoxide, or imide moiety.
  • leaving group is defined as that portion of the chemiluminescent compound susceptible to attack by molecular oxygen, hydrogen peroxide, or organic peroxides to form an intermediate that decays to produce chemiluminescence.
  • the compound includes an ester, thioester, amide, or comparable functional group derived from condensation of an acid function, although other compounds are intended to be within the scope of the present invention.
  • the chemiluminescent compound includes a functional group derived from condensation of an acid function, the bond that is broken is the single bond between the carbon and the substituted oxygen (in an ester) or nitrogen (in an amide); i.e., the C-O bond in a -COOH group.
  • carbonyl group remains with the conjugated aromatic ring; it is electronic transitions within the portion of the molecule bearing the conjugated aromatic ring that eventually produce light.
  • the remainder of the ester, amide, or comparable function constitutes the leaving group.
  • the stability of the leaving group is important in obtaining efficient chemiluminescence, i.e., a
  • the present invention encompasses a number of leaving groups not previously known to be used in chemiluminescent molecules.
  • five-membered ring including at least one heteroatom, exhibit chemiluminescent quantum yields than which are equivalent to or higher than previously described
  • chemiluminescent compounds This class of molecules is represented generically by the structure:
  • bracketed portion of the molecule includes A + , a positively charged moiety capable of producing light by chemiluminescence attached by a valence bond to a leaving group F.
  • a + is a polycyclic aromatic moiety containing a quaternary nitrogen atom. The anion associated with the quaternary
  • nitrogen atom is typically sulfate; methosulfate; perhalomethosulfate; haloborate; halophosphate;
  • halosulfonate haloacetate; phosphate; halide; phosphite; nitrate; carbonate; or bicarbonate.
  • the anion is CF 3 SO 3 - or FSO 3 -.
  • the leaving group F can be: (a) a vinyl ester; (b) a vinyl ester in which the terminal vinylic carbon is substituted with C 1 -C 5 alkyl; or, preferably (c) a moiety having the following structure (Structure II):
  • Z' can be O, S, NH, NOH, or NOR', where R' is C 1 -C 5 alkyl.
  • R' is C 1 -C 5 alkyl.
  • Z' is O.
  • X is O, S, Se, Te, or NR", where R" is
  • Q is a five-membered unsaturated ring containing a heteroatom, the five-membered unsaturated ring being of Structure III or IV:
  • R' is hydrogen or C 1 -C 5 alkyl.
  • Y is S.
  • a 2 , A 3 , and A 4 can be independently chosen from the following: a valence bond, C 1 -C 10 alkyl, C 2 -C 10 alkenyl, C 2 -C 10 alkynyl, C 3 -C 12 cycloalkyl, C 5 -C 12 cycloalkenyl, and aryl.
  • a valence bond C 1 -C 10 alkyl
  • C 2 -C 10 alkenyl C 2 -C 10 alkynyl
  • C 3 -C 12 cycloalkyl C 5 -C 12 cycloalkenyl
  • aryl As used herein in the
  • aryl refers to unsubstituted or substituted aromatic moieties containing a single unfused benzene ring
  • alkyl alkenyl
  • alkynyl alkynyl
  • cycloalkyl alkenyl
  • cycloalkenyl refer to unsubstituted or substituted groups.
  • the carbon-containing groups can themselves be substituted.
  • at least one of the carbon atoms of any of A 2 , A 3 , or A 4 (other than the carbon atom directly attached to Z 2 , Z 3 , or Z 4 and most distant from the five-membered ring) can be substituted with a
  • the carbon atom most distant from the five-membered ring is the carbon atom separated from the ring by the greatest possible number of carbon atoms of A 2 , A 3 , or A 4 .
  • a 2 is a propyl (C 3 ) group
  • the carbon atom most distant from the five-membered ring is
  • the substituents can be any of the following: hydroxy, halo, alkoxy, amino, alkylamino, arylamino, carboxyl, carboxyester, carboxythioester, thiocarboxyester, sulfonyl, nitro, sulfonic acid,
  • unsubstituted straight-chain aliphatic group such as, for example, an alkyl, alkenyl or alkynyl group, at least one of the saturated carbon atoms of A 2 , A 3 , or A 4 (other than the carbon atom directly attached to Z 2 , Z 3 , or Z 4 and most distant from the five-membered ring as defined above) can be replaced with a replacement moiety.
  • the replacement moiety can be -O-, -NH-, or -NL-.
  • L can be alkyl, cycloalkyl, oxo, hydroxy, sulfo, sulfoester, carboxyester, phosphoryl, or phosphorylester.
  • a 2 , A 3 , or A 4 is a benzyl or aryl group
  • at least one of the aromatic carbon atoms of A 2 , A 3 , or A 4 can be replaced with a replacement moiety.
  • L' can be C,C 5 alkyl, C 3 -C 12 cycloalkyl, oxo, or hydroxyalkyl.
  • Each of Z 2 , Z 3 , or Z 4 can independently be chosen from any of the following: hydrogen, carboxyl, carboxyl halide, sulfonyl halide, carboalkoxy, carboxyl acylate, carboxamido, cyano, carboxime, isocyanato, sulfo, N-succinimidylcarboxyl, or N-maleimido.
  • these groups are reactive and can be utilized to couple the chemiluminescent label to the molecule to be labeled, such as, for example, an antigen or antibody. See, for example: (a) EPO No.
  • a + and Y are as described above.
  • the sulfonamide group is relatively resistant to hydrolysis and does not require the protection of additional bulky groups such as A 2 , A 3 , and A 4 .
  • Chemiluminescent sulfonamides are
  • a second ring structure in addition to the unsaturated heterocyclic five-membered ring can be formed and two of the terminal groups Z 2 , Z 3 , and Z 4 can be eliminated, forming one of the structures depicted below as Structures VI-XI.
  • This second ring structure contains at least five atoms.
  • the additional ring structure can be formed where one of A 2 , A 3 , or A 4 is a valence bond and the other of A 2 , A 3 , or A 4 involved in the formation of the second ring is one of the following groups:
  • an alkyl, alkenyl or alkynyl group in which at least one of the saturated carbon atoms other than the carbon atom located furthest from the original unsaturated heterocyclic five-membered ring is replaced with any of -O-, -NH-, or -NL-, in which L is C 1 -C 5 alkyl; C 3 - C 8 cycloalkyl; oxo; hydroxy; sulfo; sulfoester;
  • the carbon atom located furthest from the original unsaturated heterocyclic five-membered ring is the carbon atom separated from the ring by the greatest pos-sible number of carbon atoms, as explained above for the moiety Q.
  • the additional ring is formed in this alternative when the terminal carbon of the group A 2 , A 3 or A 4 is linked by the valence bond to the five-membered unsaturated ring of Q.
  • the Polycyclic Aromatic Moiety The polycyclic aromatic moiety, A + , is
  • substituted acridinium moiety and “substituted phenanthridinium moiety” encompass the full range of possible
  • aromatic moiety can be a quinolinium or benzacridinium moiety.
  • the quinolinium or benzacridinium moiety can be substituted analogously to the acridinium or
  • a + is an acridinium moiety of
  • a 1 can be:
  • At least one of the carbon atoms can be substituted with a substituent.
  • the substituent can be hydroxy, halo, alkoxy, amino, alkylamino, arylamino, carboxyl, carboxylester, carboxylthioester,
  • thiocarboxylester sulfonyl, nitro, sulfonic acid, sulfoester, sulfinyl, cyano, isothiocyano, ureido, oxo, imino, mercapto, carboxamide, alkylthio, mercaptoester, phosphoryl, or phosphorylester.
  • a 1 is a substituted or unsubstituted straight-chain aliphatic group
  • at least one of the saturated carbon atoms of A 1 can be replaced with a replacement moiety.
  • the replacement moiety can be -O-; -NH-; or -NL-, where L is alkyl, cycloalkyl, oxo, hydroxy, sulfo, sulfoester,
  • a 1 is a benzyl or aryl group
  • at least one of the aromatic carbon atoms of A. can be replaced with a replacement moiety.
  • Z 1 can be a hydrogen, methyl, or chemically reactive group.
  • this chemically reactive group is carboxyl, carboxylhalide, sulfonylhalide, carboalkoxy, carboxy acylate, carboxamido, cyano, carboxime,
  • a 1 is a valence bond
  • Z 1 is not hydrogen.
  • a 1 is a valence bond and Z 1 is methyl.
  • R 1 , R 3 , R 5 , R 7 , and R 9 is a valence bond for attachment to the remainder of the compound.
  • the remainder of R 1 , R 3 , R 5 , R 7 , and R 9 can be independently either hydrogen or a moiety A-Z where both A and Z in the A-Z moiety are defined as A 1 and Z, as above,
  • each A and Z in the A-Z moiety can be selected independently for each of R 1 , R 3 , R 5 , R 7 , and R 9 .
  • R 5 is a valence bond, with R 1 , R 3 , R 7 , and R 9 being hydrogen.
  • R 2 , R 4 , R 6 , and R 8 can be either hydrogen or a moiety A-Z as defined in the preceding paragraph.
  • the moiety A-Z can be selected independently for each of R 2 , R 4 , R 6 , and R 8 .
  • all of R 2 , R 4 , R 6 , and R 8 are hydrogen.
  • R 14 , R 17 , and R 18 can be independently hydrogen or a moiety A-Z, defined as above.
  • the A and Z can be selected independently for each of R 14 , R 17 , and R 18 .
  • each of R 10 , R 11 , R 12 , R 13 , R 15 , and R 16 is either a hydrogen or a moiety A-Z as defined above.
  • each of R 10 , R 1 1 , R 12 , R 13 , R 15 , and R 16 is hydrogen.
  • a + is an acridinium moiety represented by Structure XII where A 1 is a valence bond; Z 1 is methyl; R 5 is a valence bond; each of R 1; R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , and R 9 is hydrogen; Z' is O; F is represented by Structure II (X-Q) where X is O; and Q is represented by the five-membered ring of Structure III
  • each of A 2 , A 3 , and A 4 are valence bonds
  • Z 2 , Z 3 , and Z 4 can be one of the following set of alternatives:
  • each of Z 2 , Z 3 , and Z 4 is hydrogen
  • Z 2 is COOC 2 H 5 and each of Z 3 and Z 4 is hydrogen;
  • Z 2 is COOCH 3
  • Z 3 is COOC 2 H 5
  • Z 4 is hydrogen
  • each of Z 2 and Z 3 is COOCH 3 and Z 4 is hydrogen;
  • each of Z 2 and Z 3 is COOCH 3 and Z 4 is CH 3 ;
  • Z 2 is COOC 2 H 5 , Z 3 is carboxyl, and Z 4 is methyl;
  • one of Z 2 , Z 3 , and Z 4 is methyl, the others being hydrogen;
  • Z 2 and Z 4 are each hydrogen and Z 3 is phenyl
  • Z 2 and Z 3 are each COOCH 3 and Z 4 is Br.
  • each of Z 2 , Z 3 , and Z 4 is hydrogen.
  • Preferred chemiluminescent acridinium salts according to the present invention accordingly have the following structure (Structure XIV):
  • the present invention also encompasses chemiluminescent sulfonamide derivatives comprising a cation and an anion.
  • the cation has the general
  • the increased resistance of the sulfonamide to hydrolysis means that bulky protecting groups in the five-membered unsaturated heterocyclic ring are not required.
  • a + is a positively charged moiety capable of producing light by
  • chemiluminescence which can be acridinium, substituted acridinium, phenanthridinium, substituted
  • a + is N-methylacridinium.
  • R' is hydrogen or C 1 -C 5 alkyl.
  • Y is S.
  • the anion is as described above.
  • the anion is CF 3 SO 3 - or FSO 3 -
  • a preferred chemiluminescent sulfonamide derivative according to the present invention has the structure shown below as Structure XVI.
  • chemiluminescent compounds capable of covalent attachment to a biologically active molecule are also within the scope of the invention. These comprise a chemical group that can produce light by chemiluminescence coupled to a leaving group containing phosphorus, sulfur, or carbon double-bonded to C, N or O. If phosphorus or sulfur is part of the leaving group, it is in a relatively polar moiety in which the phosphorus or sulfur is bonded to more electronegative atoms.
  • the leaving groups include the following structures
  • R 1 can be any of:
  • R 2 can be any of:
  • R 3 can be O, S, NH, NR 1 , NR 2 , CH 2 , C(R 1 ) 2 , C(R 2 ) 2 , or CR 1 R 2 , where R 1 and R 2 are defined as in the preceding two paragraphs.
  • the chemical group that can produce light by chemiluminescence is a heterocyclic ring or ring system.
  • the ring or ring system can be acridinium, phenanthridinium, quinolinium, or
  • chemiluminescent labels of the type disclosed in this section the preferred chemical group that can produce light by chemiluminescence is an
  • the leaving group is preferably either , in which R 1 is pyrrole and R 3 is pyrazole, or
  • chemiluminescent compounds as disclosed in Section I, above can be prepared by reacting an acyl chloride derivative, or other comparably reactive
  • the reaction is a condensation between the activated carboxyl function and a hydroxyl, mercapto, or similar function of the leaving group.
  • the reaction is preferably performed in a
  • chlorinated methane such as dichloromethane or
  • acridine derivative is then quaternized by reacting the derivative with a methylating agent such as, for example, methyl
  • chemiluminescent compounds In order for the chemiluminescent compounds to be used as labels in immunoassays, as well as other analytical assays, it is necessary to attach the compound covalently to the biological molecule to be measured or to a biological molecule reacting specifically with the biological molecule to be measured.
  • Typical biological molecules or biomolecules to which the chemiluminescent compounds of the present invention can be attached include, for example, peptides, haptens, antigens, antibodies, enzymes, receptor proteins, hormones,
  • oligonucleotides oligonucleotides, nucleic acids, therapeutic drugs, and drugs of abuse.
  • compound contains a reactive group such as, for example, carboxyl, carboxyl halide, sulfonyl halide, carboalkoxy, carboxamido, carboxime, or N-succinimidylcarboxy, such groups can be coupled covalently to hydroxyl functions or amino functions using conjugation reagents such as, for example, carbodiimides or 1,1-carbonyldiimidazole.
  • a reactive group such as, for example, carboxyl, carboxyl halide, sulfonyl halide, carboalkoxy, carboxamido, carboxime, or N-succinimidylcarboxy, such groups can be coupled covalently to hydroxyl functions or amino functions using conjugation reagents such as, for example, carbodiimides or 1,1-carbonyldiimidazole.
  • N-maleimido groups react directly with sulfhydryl
  • labels according to the present invention produce chemiluminescence by reaction with hydrogen peroxide, molecular oxygen or an organic peroxide in an alkaline solution.
  • the pH of the solution has a range from about 7 to about 14; preferably, the pH is at least 10; most preferably, the pH is about 13.
  • organic peroxide can be used, including, for example, perbenzoic acid, benzyl peroxide, or t-butyl hydroperoxide.
  • Chemiluminescence is typically measured at 425-430 nm in a commercially available luminometer, such as a Berthold Chemiluminometer produced by Berthold
  • a quantity of acridine-9-acyl chloride (1940 mg) was placed in a 100 ml round-bottom flask with a stirring bar. Dry CHCl 3 (15 ml) was added to dissolve the solid acid chloride. Triethylamine (1300 ⁇ l) and
  • the solvent was then removed by distillation at a pot temperature of 90-100°C.
  • the flask was then cooled and the residue was triturated with approximately 25 ml cyclohexane .
  • the residue initially a dark brown oil, became a yellow solid; the solid was filtered and washed with cyclohexane.
  • the yellow solid was dissolved in heated methane and dried onto 8 g of silica gel.
  • the silica gel was placed in a 2.5 ⁇ 60 cm column packed with 110 g silica gel slurried with chloroform. The column was eluted sequentially with chloroform, 98%
  • the reaction vessel was flushed with nitrogen gas, capped, and then placed in the dark for 2-3 days, after which period of time crystals were observed on the bottom of the flask.
  • the solution was filtered, and 70 mg of a solid was obtained. This solid was designated R171TD.
  • the product was quaternized by placing 50 mg in a 10-ml round-bottom flask, dissolving in 3 ml of dry methylene chloride, and adding 200 ⁇ l of methyl
  • the product had a melting point of >250°C.
  • Mass spectroscopy gave a quasi-molecular ion corresponding to the anticipated M + at M/Z 450. Because the compound is a quaternary nitrogen salt it has a pre-existing positive charge and does not acquire an extra proton from the matrix ionization. Also, the negatively charged
  • a quantity of acridine-9-carboxylic acid (22.3 g; 0.1 mol) was placed in a 250-ml round-bottom flask. Freshly distilled thionyl chloride (70 g; 42 ml) was added, and the resulting reaction mixture was heated under reflux for 3 hours, yielding acridine-9-carboxylic acid chloride hydrochloride. The excess of thionyl chloride was removed by distillation and the traces left were removed by washing with dry benzene. The solid acid chloride was kept under dry benzene. It was collected by filtration to give the acid chloride as a yellow solid. The yield was 24.7 g, or 90%.
  • the acridine acid chloride (0.277 g; 1 mmol) was dissolved in 20 ml of dry chloroform in a round-bottom flask. Pyrrole (67 mg; 1 mmol) was added, followed by addition of triethylamine (0.30 g; 0.32 ml; 3 mmol). The reaction mixture was left overnight with stirring. The solvent was removed under reduced pressure and the residue was dissolved in water and extracted with ethylacetate. Thin-layer chromatography on silica gel in hexane-ethyl acetate (70:30) showed a major fluorescent spot, the product.
  • 9-(N-pyrryl)carbonyl acridine was achieved using silica gel column chromatography using hexane-ethyl acetate as eluant to yield 165 mg (61%).
  • the 9-(N-pyrryl)carbonyl acridine was converted to 9-(N-pyrryl)carbonyl-N-methylacridinium fluorosulfonate by treatment with methyl fluorosulfonate.
  • a quantity of the acridine compound (1.36 mg; 0.5 mmol) was dissolved in 20 ml of dry
  • the substituted acridine was converted to 9-(2-pyrazolyl)carbonyl-N-methylacridinium fluorosulfonate by treatment with methyl fluorosulfonate as in Example 3.
  • the reaction used 0.273 g (1 mmol) of the substituted acridine along with 20 ml of CH 2 Cl 2 and 1 ml of methylfluorosulfonate.
  • the yield was 310 mg (80%).
  • the compound 9-(N-2-methylindolyl)carbonyl-N-methylacridinium fluorosulfonate was prepared essentially as in Examples 3 and 4, starting with acridine acid chloride and 2-methylindole.
  • the reaction mixture comprised 1.385 g of acridine acid chloride (5 mmol), 0.655 g of 2-methylindole (5 mmol), and 1.515 g of triethylamine (15 mmol), in 50 ml of dry chloroform.
  • methylfluorosulfonate was purified by dissolving in distilled water, filtration, and evaporation until dryness to yield a dark yellow semi-solid product.
  • Fluorosulfonate 9-(N-isatinyl)carbonyl-N-methylacridinium fluorosulfonate was prepared essentially as in Examples 3-5 starting with acridine acid chloride, isatin and triethylamine.
  • the reaction mixture comprised 1.4 g of acridine acid chloride (5 mmol), 0.4 g of isatin (5 mmol), and 1.51 g of triethylamine (15 mmol) in 50 ml of dry chloroform.
  • the yield after column chromatography on silica gel using ethylacetate-hexane (80:20) was 0.64 g (36%) as a pale yellow semi-solid product.
  • This product 9-(N-isatinyl)carbonyl acridine, was converted to the N-methylfluorosulfonate by reaction with methylfluorosulfonate as in Examples 3-5.
  • the reaction product was a dark brown gum. It was purified by dissolving in distilled water and filtration from the brown impurities. The water was evaporated under reduced pressure. The product was dried, washed with n-hexane, and dried to give a yellow solid.
  • the present invention provides chemiluminescent compounds with quantum yield and stability equal to or exceeding the quantum yield and stability of presently available compounds that are suitable for use in labeling biological molecules.
  • the compounds are particularly suitable for conjugation to biomolecules such as

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Abstract

De nouveaux composés chimioluminescents sont appropriés pour être utilisés dans le marquage de molécules biologiques pour des analyses telles que des immunoanalyses. Ces marques chimioluminescentes se caractérisent par l'incorporation de groupes partants stables. Une classe de ces marques chimioluminescentes comprend des sels dans lesquels le groupe partant contient un atome de carbone carboxyle ou son équivalent isoélectronique et un cycle à cinq membres, y compris au moins un hétéroatome. L'hétéroatome est de préférence de l'oxygène ou du soufre. Ce groupe partant est lié à une fraction chargée positivement pouvant produire de la lumière par chimioluminescence, et peut-être une fraction d'acridinium, phénanthridinium, quinolinium ou benzacridinium. Tant le groupe partant que la fraction chargée positivement peuvent être substitués, par exemple avec des substituants réactifs pour associer de manière covalente l'étiquette ou marque à une molécule biologique. Des substituants sur le cycle à cinq membres du groupe partant peuvent former un cycle additionnel. Une classe additionnelle de ces marques chimioluminescentes comprend un groupe chimique qui peut produire de la lumière par chimioluminescence et relié par covalence à un groupe partant comprenant une fraction contenant un atome de soufre, de phosphore ou de carbone lié par une double liaison à un ou plusieurs atomes électronégatifs.
PCT/US1991/006861 1990-11-21 1991-09-20 Composes chimioluminescents WO1992009580A1 (fr)

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Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1995019976A1 (fr) * 1994-01-25 1995-07-27 Biocode S.A. Derives chemoluminescents heterocycliques
US5731148A (en) * 1995-06-07 1998-03-24 Gen-Probe Incorporated Adduct protection assay
FR2763691A1 (fr) * 1997-05-22 1998-11-27 Hoffmann La Roche Procede ameliore d'analyse immunologique par polarisation de fluorescence
WO2002099097A1 (fr) * 2001-06-01 2002-12-12 Roche Diagnostics Gmbh Nouveaux composes destines a des procedes de chimioluminescence
JP2003517426A (ja) * 1997-08-21 2003-05-27 メイン メディカル センター 過酸化物に基づく化学発光の検量方法、並びにそのために用いる化合物
US10290812B2 (en) 2014-11-25 2019-05-14 Samsung Electronics Co., Ltd. Compound for organic photoelectric device and organic photoelectric device image sensor, and electronic device including the same

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Publication number Priority date Publication date Assignee Title
GB1461877A (en) * 1974-02-12 1977-01-19 Wellcome Found Assay method utilizing chemiluminescence
EP0082636A1 (fr) * 1981-12-11 1983-06-29 The Welsh National School of Medicine Composés et procédé pour le marquage luminescent
EP0257541A2 (fr) * 1986-08-22 1988-03-02 Hoechst Aktiengesellschaft Dérivés de l'acridine chimioluminescents et leur utilisation pour dosage immunologique par chimioluminescence
EP0330050A2 (fr) * 1988-02-20 1989-08-30 Hoechst Aktiengesellschaft Dérivés spéciaux d'acridine chimiluminescents et leur utilisation dans des tests d'immunoluminescence

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB1461877A (en) * 1974-02-12 1977-01-19 Wellcome Found Assay method utilizing chemiluminescence
EP0082636A1 (fr) * 1981-12-11 1983-06-29 The Welsh National School of Medicine Composés et procédé pour le marquage luminescent
EP0257541A2 (fr) * 1986-08-22 1988-03-02 Hoechst Aktiengesellschaft Dérivés de l'acridine chimioluminescents et leur utilisation pour dosage immunologique par chimioluminescence
EP0330050A2 (fr) * 1988-02-20 1989-08-30 Hoechst Aktiengesellschaft Dérivés spéciaux d'acridine chimiluminescents et leur utilisation dans des tests d'immunoluminescence

Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1995019976A1 (fr) * 1994-01-25 1995-07-27 Biocode S.A. Derives chemoluminescents heterocycliques
BE1008216A4 (fr) * 1994-01-25 1996-02-20 Biocode Sa Derives chemoluminescents heterocycliques.
US5731148A (en) * 1995-06-07 1998-03-24 Gen-Probe Incorporated Adduct protection assay
FR2763691A1 (fr) * 1997-05-22 1998-11-27 Hoffmann La Roche Procede ameliore d'analyse immunologique par polarisation de fluorescence
JP2003517426A (ja) * 1997-08-21 2003-05-27 メイン メディカル センター 過酸化物に基づく化学発光の検量方法、並びにそのために用いる化合物
US7718576B2 (en) 1997-08-21 2010-05-18 Waldrop Iii Alexander A Peroxide-based chemiluminescent assays and chemiluminescent compounds used therein
JP4838932B2 (ja) * 1997-08-21 2011-12-14 メイン メディカル センター 過酸化物に基づく化学発光の検量方法、並びにそのために用いる化合物
WO2002099097A1 (fr) * 2001-06-01 2002-12-12 Roche Diagnostics Gmbh Nouveaux composes destines a des procedes de chimioluminescence
US7332354B2 (en) 2001-06-01 2008-02-19 Roche Diagnostics Operations, Inc. Compounds for chemiluminescense procedures
US10290812B2 (en) 2014-11-25 2019-05-14 Samsung Electronics Co., Ltd. Compound for organic photoelectric device and organic photoelectric device image sensor, and electronic device including the same

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