Drug – bio-affecting and body treating compositions – Antigen – epitope – or other immunospecific immunoeffector – Conjugate or complex
Reexamination Certificate
1995-08-22
2004-10-12
Wortman, Donna C. (Department: 1648)
Drug, bio-affecting and body treating compositions
Antigen, epitope, or other immunospecific immunoeffector
Conjugate or complex
C436S501000, C436S518000, C436S543000, C530S403000, C530S388900, C530S398000, C435S007100, C435S007900
Reexamination Certificate
active
06803040
ABSTRACT:
FIELD OF THE INVENTION
This invention is in the field of ligand receptor assays, including immunoassays, for the detection of tricyclic antidepressants and selected metabolites of tricyclic antidepressants in a fluid sample. More particularly, this invention relates to methods for the synthesis of novel tricyclic antidepressant derivatives and protein and polypeptide tricyclic antidepressant derivative conjugates and labels for use in the preparation of antibodies to tricyclic antidepressant metabolites and for use in the immunoassay process.
BACKGROUND OF THE INVENTION
Tricyclic antidepressants have been used to treat endogenous depression since 1957. The therapeutic dose of tricyclic antidepressants varies from person to person and to achieve an effective dose for a patient, a simple and accurate methodology is required for the measurement of tricyclic antidepressants and their metabolites in blood and urine. In addition, doses of tricyclic antidepressants above the therapeutic amount can cause toxic side effects and death. Thus, a medical need exists for antibodies and diagnostics to rapidly detect tricyclic antidepressants and tricyclic antidepressant metabolites in order to monitor tricyclic antidepressant therapy and treat tricyclic antidepressant overdose.
The preparation of antibodies to tricyclic antidepressants and tricyclic antidepressant metabolites requires the synthesis of tricyclic antidepressant derivatives in order to covalently attach the derivative to an antigenic polypeptide or protein. In addition, the tricyclic antidepressant derivative is covalently attached to various polypeptides, proteins or labels for use in screening antibodies and in the immunoassay process. The tricyclic antidepressant derivative should mimic the structure of the tricyclic antidepressant metabolites sought to be measured. Therefore, the selection and synthesis of the types of tricyclic antidepressant derivatives for covalent attachment to proteins, polypeptides or labels are critical. In addition, the tricyclic antidepressant derivatives need to be stable and soluble in an aqueous solution.
Tricyclic antidepressant compounds and conjugates for immunization and immunoassay have been described in U.S. Pat. Nos. 4,223,013, 4,275,160, 4,307,245,4,629,691 and 4,772,697 and a European Patent Application No. 86113654.7.
SUMMARY OF THE INVENTION
The present invention is directed to novel tricyclic antidepressant derivatives which are synthesized for the covalent attachment to antigens (proteins or polypeptides) for the preparation of antibodies to tricyclic antidepressants and tricyclic antidepressant metabolites. The resulting novel antigens may be used for the production of antibodies using standard methods. Once generated, the antibodies and the novel derivatives which are covalently attached to proteins, polypeptides or labels may be used in the immunoassay process.
DEFINITIONS
In accordance with the present invention and as used herein, the following terms, are defined with the following meanings, unless explicitly stated otherwise.
“Drug” shall mean any compound or ligand which either as a result of spontaneous chemical reaction or by enzyme catalyzed or metabolic reaction, generates an intrinsic activity when administered to a biological system. The drug may be metabolized to a derivative of the drug by a biological system. Common examples of drugs and their metabolites are tricyclic antidepressants, morphine, barbiturates, tetrahydrocannabinol, phencyclidine, amphetamines, methamphetamines, opiates, benzodiazepines, cocaine, estrone-3-glucuronide, pregnanediol-glucuronide, cotinine, lysergic acid diethylamide, methadone, propoxyphene, anabolic steroids.
“Drug derivative” shall mean a ligand derivative, drug, drug metabolite or a drug analogue conjugated to a linking group.
“Drug metabolite” shall mean a compound upstream or downstream from a drug in a biochemical or metabolic pathway, or an intermediate.
“Label” shall mean a signal development element or a means capable of generating a signal, for example, a dye or an enzyme. The attachment of a drug derivative to the label can be through covalent bonds, adsorption processes, hydrophobic and/or electrostatic bonds, as in chelates and the like, or combinations of these bonds and interactions.
“Binding domain” shall refer to the molecular structure associated with that portion of a receptor that binds ligand. More particularly, the binding domain may refer to a polypeptide, natural or synthetic, or nucleic acid encoding such a polypeptide, whose amino acid sequence represents a specific region of a protein, said domain, either alone or in combination with other domains, exhibiting binding characteristics which are the same or similar to those of a desired ligand/receptor binding pair. Neither the specific sequences nor the specific boundaries of such domains are critical, so long as binding activity is exhibited. Likewise, used in this context, binding characteristics necessarily includes a range of affinities, avidities and specificities, and combinations thereof, so long as binding activity is exhibited.
“Linking group” shall mean the “chemical arm” between the protein, polypeptide or label and a drug or drug derivative. As one skilled in the art will recognize, to accomplish the requisite chemical structure, each of the reactants must contain the necessary reactive groups. Representative combinations of such groups are amino with carboxyl to form amide linkages, or carboxy with hydroxy to form ester linkages or amino with alkyl halides to form alkylamino linkages, or thiols with thiols to form disulfides, or thiols with maleimides or alkylhalides to form thioethers. Obviously, hydroxyl, carboxyl, amino and other functionalities, where not present may be introduced by known methods. Likewise, as those skilled in the art will recognize, a wide variety of linking groups may be employed. The structure of the linkage should be a stable covalent linkage formed to attach the drug or drug derivative to the protein, polypeptide or label. In some cases the linking group may be designed to be either hydrophilic or hydrophobic in order to enhance the desired binding characteristics of the ligand and the receptor. The covalent linkages should be stable relative to the solution conditions under which the ligand and linking group are subjected. Generally preferred linking groups will be from 1-20 carbons and 0-10 heteroatoms (NH, O, S) and may be branched or straight chain. Without limiting the foregoing, it should be obvious to one skilled in the art that only combinations of atoms which are chemically compatible comprise the linking group. For example, amide, ester, thioether, thioester, keto, hydroxyl, carboxyl, ether groups in combinations with carbon-carbon bonds are acceptable examples of chemically compatible linking groups. Other chemically compatible compounds which may comprise the linking group are set forth in this Definition section and hereby are incorporated by reference.
“Hydrocarbyl” shall refer to an organic radical comprised of carbon chains to which hydrogen and other elements are attached. The term includes alkyl, alkenyl, alkynyl and aryl groups, groups which have a mixture of saturated and unsaturated bonds, carbocyclic rings and includes combinations of such groups. It may refer to straight-chain, branched-chain cyclic structures or combinations thereof.
“Aryl” shall refer to aromatic groups which have at least one ring having a conjugated pi electron system and includes carbocyclic aryl, heterocyclic aryl and biaryl groups, all of which may be optionally substituted.
“Carbocyclic aryl groups” shall refer to groups wherein the ring atoms on the aromatic ring are carbon atoms. Carbocyclic aryl groups include monocyclic carbocyclic aryl groups and optionally substituted naphthyl groups.
“Monocyclic carbocyclic aryl” shall refer to optionally substituted phenyl, being preferably phenyl or phenyl substituted by one to three substituents, such being advantageously lower alkyl, hydroxy, lower alkoxy, lower alkanoyloxy, haloge
Buechler Kenneth Francis
Noar Joseph Barry
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