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United States Patent [191 [L 1] 4,045,420 Softer Et A1

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United States Patent [191 [L 1] 4,045,420 Softer Et A1 United States Patent [191 [l 1] 4,045,420 Softer et a1. [45] Aug. 30, 1977 [54] NON-OXO-CARBONYL CONTAINING [561 References Cited BENZOYL ECGONINE AND COCAINE U.S. PATENT DOCUMENTS COMPOUNDS POLYPEPTIDE AND DERIVATIVES THEREOF 3,690,834 9/1972 Goldstein et a1. ............... .. 23/230 R 3,888,866 6/1975 Leute et a1. .......... .. 260/292 [75] Inventors: Michael J. Suffer, Redwood City; 3,966,744 6/1976 Goldstein et a1. 260/292 Richard S. Schneider, Saratoga, both Primary Examiner-Howard E. Schain of Calif. Attorney. Agent, or Firm-Townsend and Townsend [51] ABSTRACT Assignee: Syva Company, Palo Alto, Calif. [73] Non-oxo-carbonyl substituted derivatives of cocaine are provided for conjugation with other compounds to l2 l] Appl. No.: 364,842 provide reagents for use in a diversity of immunoassay techniques. Specifically, carboxy or imidoyl derivatives [22] Filed: May 29, 1973 are provided which may be conjugated with antigens for use in the preparation of antibodies to cocaine or [51] Int. Cl.2 .............................................. .. C07G 7/00 conjugated with detector molecules for use in the quali [52] US. Cl. ................................ .. 260/112 R; 195/63; tative or quantitative determination of the presence of 195/68; 195/1035 R; 260/78 A; 260/1125 R; cocaine. 260/121; 260/292; 424/85; 424/88; 23/230 B [53] Field of Search ................ .. 260/112 R, 292, 78 A 6 Claims, No Drawings 4,045,420 1 2 substituted stable free radicals to provide a detector NON-OXO-CARBONYL CONTAINING BENZOYL molecule for use in FRAT®. ECGONINE AND COCAINE COMPOUNDS POLYPEPTIDE AND DERIVATIVES THEREOF DESCRIPTION OF THE SPECIFIC EMBODIMENTS BACKGROUND OF THE INVENTION The compounds of this invention are derivatives of 1. Field of the Invention nor-tropane which are able to be used for preparing A wide variety of ways have been developed for antibodies to cocaine, as well as be bonded to detector determining minute quantities of various organic com molecules for use in immunoassays; pounds. A number of methods which can be used for Ecgnonine is Z-carboxy-B-hydroxytropane. Cocaine the determination of organic compounds depend on the is the methyl ester of 2-carboxy-3-hydroxytropane ben-‘ availability of a receptor which recognizes a particular zoate. The derivatives of this invention will be either at compound or class of compounds. The most common the 3 position, or the 8 position of the nor-tropane ring. type of receptor is the antibody which is able to strongly bind to a particular spatial conformation and For the most part, the compounds of this invention polar or non-polar distribution. will be of from 10 to 25 carbon atoms and from 6 to 7 In order to prepare the antibodies for compounds heteroatoms which will be oxygen and nitrogen. More which are not antigenic, the non-antigenic compound is usually, the compounds of this invention will be of from normally bonded to an antigenic material, particularly a 16 to 22 carbon atoms and from 6 to 7 heteroatoms, protein. With most compounds, it is found necessary to 20 which are oxygen and nitrogen. There will usually be modify the compound of interest to bond to the antigen. from 0 to 2 sites of ethylenic unsaturation, more usually In addition, in some of the immunoassays, it is neces from 0 to 1 site of ethylenic unsaturation. The hetero sary to bond the compound to a detector molecule. The functionalities will be limited to non-oxo-carbonyl and link that is chosen for bonding to the antigen and to the nitrogen analogs thereof, and amino. The non-oxo-car 25 detector molecule must allow not only for satisfactory bonyl functionalities include esters, carboxyic acids, bonding to the various molecules, but also must provide carboxylic acid anhydrides, and imidates. an antibody which recognizes the compound when it is For the most part, the compounds of this invention bound to the detector molecule. will have the following formula: In addition, the linking group must not signi?cantly 30 change the polar characteristics of the compound to be assayed nor detrimentally affect the molecules to which the compound is bonded. Depending on the particular material to which the compound is to be bonded, the linking group should permit a sufficient number of the 35 desired compound to be bonded to the antigen or detec tor molecule. Additional considerations include syn thetic simplicity, chemical stability, the effect of the wherein A is hydrogen or methyl; bonding functionality on the material to which it is one of Y and Y’ is hydrocarbylene; aliphatic, alicy bonded, and the particular site on the material for exam ple, a protein, to which the compound will be bonded. clic, aromatic or combinations thereof, of from 1 to 10 2. Description of the Prior Art carbon atoms, more usually of from 1 to 8 carbon atoms, An immunoassay technique employing a stable free wherein Y-X is methyl when Y’ is hydrocarbylene and radical detector, entitled FRAW, supplied by Syva Y'X is phenyl or hydrogen when Y is hydrocarbylene; Corporation, is described in US. Pat. No. 3,690,834. 45 X, when bonded to a hydrocarbylene, is a non-0x0 Another immunoassay technique using enzymes as a carbonyl functionality, including nitrogen analogs detector and commercially available as EMITTM, sup thereof, including carboxylic acid, carboxylic acid es plied by Syva Corporation, is found in copending appli ters of from 2 to 8 carbon atoms, imidates of from 1 to cation, Ser. No. 143,609 ?led May 14, 1971 now aban 8 carbon atoms, more usually from 1 to 4 carbon atoms, doned. Radio-immunoassay is described in a number of 50 and mixed anhydrides, particularly carbonic acid anhy texts for example Kirkham, et al, Radioimmunoassay dride, of from 3 to 10 carbon atoms, more usually 3 to 8 Methods, Churchill, Livingston, London, 1971. A de carbon atoms; and a scription of a number of derivatives of cocaine and a is zero when Y'X is hydrogen and one when Y'X is ecgonine may be found in Pelletier, Chemistry of the other than hydrogen. Alkaloids, Van Nostrand-Reinhold, New York, 1970. 55 The hydrocarbylene may be straight chain or branched, (1.5. Pat. No. 3,498,989 also discloses a number of co usually having not more than one branch per 2 carbon caine derivatives. atoms, the branch usually being methyl. For the most SUMMARY OF THE INVENTION part, the hydrocarbylene will either be aliphatic or aromatic, generally being monocyclic. If alicyclic, the Cocaine derivatives are provided having non-0x0 60 carbonyl functionalities for bonding to amino groups, ring will normally be of from 5 to 6 carbon atoms. particularly amino groups of proteins or amino groups Illustrative hydrocarbylene groups include methy present in stable free radicals. The compounds of this lene, ethylene, butylene, hexylene, phenylene, tolylene, invention are bonded to proteins, either to provide an benzylene, cyclohexylene, propenylene, hexenylene, antigenic material for production of antibodies to ecgo 65 l,4-pentenylene, etc. nine or cocaine, or bonding to enzymes to provide a For those compounds which have the non-oxo-carbo reagent for use in immunoassays. Alternatively, the nyl derivative at the 8 position, they will, for the most compounds of this invention may be bonded to amino part, come within the following formula: 4,045,420 4 on a ring, more usually not more than 2 substituents on a ring. Of particular interest for the use of the subject com pounds are the non-oxo-carbonyl substituted cocaine or ecgonine or nitrogen analogs thereof, particularly sub stituted benzoyl ecgonine, bonded to an amino group, which is part of a polypeptide structure. One group of polypeptides is antigenic, so that by bonding the non wherein oxo-carbonyl modi?ed cocaine, ecgonine, or benzoyl ‘A1 is hydrogen or methyl, usually methyl; ecgonine to the polypeptide, antibodies can be formed 21 is hydrogen or benzoyl, usually benzoyl; to cocaine and its metabolites. A narrower class of poly Y1 is hydrocarbylene of from 1 to 10 carbon atoms, peptides which also can be used as antigens but will not more usually of from 1 to 8 carbon atoms, and usu normally be used as such, are enzymes which are em ally of from O to 1 site of ethylenic unsaturation, and ployed as the detector in an immunoassay system. may be aliphatic, alicyclic or aromatic or combina 15 Polypeptides usually encompass from about 2 to 100 tions thereof, usually aliphatic of from 1 to 6 carbon amino acid units (usually less than about 12,000 molecu atoms; lar weight). Larger polypeptides are arbitrarily called Wl is oxygen or imino (--NH--); and proteins. Proteins are usually composed of from 1 to 20 MI is hydrogen, hydrocarbon of from 1 to 8 carbon polypeptide chains, called subunits, which are asso 20 atoms, more usually of from 1 to 6 carbon atoms, usu ciated by covalent or non-covalent bonds. Subunits are ally being other than hydrogen when A1 is hydrogen, normally of from 100 to 300 amino acid groups (approx and preferably alkyl of from 1 to 4 carbon atoms, or imately 10,000 to 35,000 molecular weight). For the alkoxycarbonyl when W1 is oxygen, so as to form a purposes of this invention, polypeptide is intended to include individual polypeptide units, or polypeptides mixed anhydride with carbonic acid. The alkyl group 25 will normally be of from 1 to 6 carbon atoms, more which are subunits of proteins, whether composed usually of from 2 to 6 carbon atoms. When M1 is alkoxy solely of polypeptide units or polypeptide units in com carbonyl, A1 will be methyl.
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