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WO1994026755A1 - Complexes d'acides bicyclopolyazamacrocyclophosphoniques, conjugues de ces derniers, procede de preparation associe et d'utilisation en tant que produits radiopharmaceutiques - Google Patents

Complexes d'acides bicyclopolyazamacrocyclophosphoniques, conjugues de ces derniers, procede de preparation associe et d'utilisation en tant que produits radiopharmaceutiques Download PDF

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Publication number
WO1994026755A1
WO1994026755A1 PCT/US1993/004356 US9304356W WO9426755A1 WO 1994026755 A1 WO1994026755 A1 WO 1994026755A1 US 9304356 W US9304356 W US 9304356W WO 9426755 A1 WO9426755 A1 WO 9426755A1
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alkyl
complex
term
terms
conjugate
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PCT/US1993/004356
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English (en)
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Garry E. Kiefer
Jaime Simon
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The Dow Chemical Company
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Priority to PCT/US1993/004356 priority Critical patent/WO1994026755A1/fr
Priority to AU42398/93A priority patent/AU4239893A/en
Publication of WO1994026755A1 publication Critical patent/WO1994026755A1/fr

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    • 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
    • C07F9/6561—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
    • A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
    • A61K51/04—Organic compounds
    • A61K51/0474—Organic compounds complexes or complex-forming compounds, i.e. wherein a radioactive metal (e.g. 111In3+) is complexed or chelated by, e.g. a N2S2, N3S, NS3, N4 chelating group
    • A61K51/0482—Organic compounds complexes or complex-forming compounds, i.e. wherein a radioactive metal (e.g. 111In3+) is complexed or chelated by, e.g. a N2S2, N3S, NS3, N4 chelating group chelates from cyclic ligands, e.g. DOTA
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
    • A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
    • A61K51/04—Organic compounds
    • A61K51/08—Peptides, e.g. proteins, carriers being peptides, polyamino acids, proteins
    • A61K51/10—Antibodies or immunoglobulins; Fragments thereof, the carrier being an antibody, an immunoglobulin or a fragment thereof, e.g. a camelised human single domain antibody or the Fc fragment of an antibody
    • A61K51/1093—Antibodies or immunoglobulins; Fragments thereof, the carrier being an antibody, an immunoglobulin or a fragment thereof, e.g. a camelised human single domain antibody or the Fc fragment of an antibody conjugates with carriers being antibodies
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2121/00—Preparations for use in therapy
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2123/00—Preparations for testing in vivo

Definitions

  • This invention concerns comDlexes that contain bicyclopoiyazamacrocyclophosphonic acid ligands with metal ions, and conjugates thereof, for use as
  • radiopharmaceuticals especially for the treatment and/or diagnosis of cancer
  • the process for the preparation of both the complexes and conjugates is provided
  • radionuclides for treatment of cancer metastatic to the bone dates back to the early 1950's. It has been proposed to inject a radioactive particle-emitting nuclide in a suitable form for the treatment of calcific lesions. It is desirable that such nuclides be concentrated in the area of the bone lesion with minimal amounts reaching the soft tissue and normal bone. Radioactive phosphorus (P-32 and P-33) compounds have been proposed, but the nuclear and biolocalization properties limit the use of these compounds. (E. Kaplan, et al., J. Nud. Med. 1(1 ), 1 , (1960); U.S. Patent 3,965,254).
  • Strontium-89 has also been proposed for patients with metastatic bone lesions.
  • the long half-life (50.4 days) high blood levels and low lesion to normal bone ratios limit the utility.
  • radionuclides for calcific tumor therapy or relief of bone pain is discussed in published European patent application 176,288, where the use of Sm- 153, Gd-159, Ho-166, Lu-177 or Yb-175 complexed with a ligand such as ethylenediaminetetraacetic acid (EDTA) or hydroxyethylenediaminetriacetic acid (HEEDTA) is disclosed.
  • EDTA ethylenediaminetetraacetic acid
  • HEEDTA hydroxyethylenediaminetriacetic acid
  • a macrocyclic system having a 1 ,4,7,10-tetraazacyclododecane moiety complexed with Sm-153, Gd-159, Ho- 166, Lu-177 or Yb-175 for calcific tumor therapy or relief of bone pain is discussed in U.S. Patent 5,059,412 which complex is very stable and has a lower charge than the complex disclosed in published European patent application 176,288.
  • Radionuclide complexes of such antibody/chelant conjugates are useful in diagnostic and/or therapeutic applications as a means of conveying the radionuclide to a cancer or tumor cell. See, for example, Meares et al., Anal. Biochem. 142, 68-78, (1984); and Krejcarek et al., Biochem. and Biophys. Res. Comm. 77, 581 -585 (1977).
  • NTA nitrilotriacetic acid
  • EDTA ethylenediaminetetraacetic acid
  • HEDTA hydroxyethylethylenediaminetriacetic acid
  • DTPA diethylenetriaminepentaacetic acid
  • CDTA trans- 1 ,2-diaminocyclohexa ⁇ etetraacetic acid
  • DOTA 1,4,7,10-tetraazacyclododecanetetraacetic acid
  • Patent 4,479,930 and mixed carboxycarbonic anhydrides of DTPA [Gansow, U.S. Patents 4,454,106 and 4,472,509; Krejcarek et al., Biochem. and Biophys.Res. Comm. 77, 581-585, (1977)] have been reported.
  • the anhydrides are coupled to proteins the coupling proceeds via formation of an amide bond thus leaving four of the original five carboxymethyl groups on the diethylenetriamine (DETA) backbone [Hnatowich et al. Int. J. AppI. Isot 33, 327-332, (1982)].
  • DETA diethylenetriamine
  • Patents 4,432,907 and 4,352,751 disclose bifunctional cheiating agents useful for binding metal ions to "organic species such as organic target molecules or antibodies. " As in the above, coupling is achieved via an amide group through the u' ization of diaminotetraacetic acid dianhydrides. Examples of anhydrides include dianhydrides of EDTA, CDTA, propylenediaminetetraacetic acid and phenyiene 1 ,2-diaminetetraacetic acid.
  • a recent U.S. Patent 4,647,447 discloses several complex salts formed from the anion of a complexing acid for use in various diagnostic techniques. Conjugation via a carboxyl group of the complexmg acid is taught which gives a linkage through an amide bond.
  • Paik et al disclose the use of p-nitrobenzyl bromide in a reaction with a "blocked" diethylenet ⁇ amine, i e b ⁇ s-(2- phthal ⁇ m ⁇ doethyl)am ⁇ ne followed by deblocking procedures and carboxymethylation using chloroacetic acid, to give N'-p-nitrobenzyldiethylenet ⁇ amine N,N,N ,N -tetraacetic acid
  • N,N,N ,N -tetraacetic acid is obtained Conjugation of the bifunctional cheiating agent and chelation with indium is discussed Substitution on the nitrogen atom is also taught by Eckelman, et al in the J. Pharm Sci 64(4), 704-706 (1975) by reacting amines such as "ethylenediamine or diethylenet ⁇ amine with the appropriate alkyl bromide before carboxymethylation "
  • the compounds are proposed as potential
  • Patents 3,994,966 and 4,043,998 It is important to note that the attachment of the aromatic group to the EDTA structure is through a carbon of the ethylenediamine backbone Optically active bifunctional cheiating agents based on EDTA, HEDTA and DTPA are disclosed in U. S.4,622,420 In these compounds an alkylene group links the aromatic group (which contains the functionality needed for attachment to the protein) to the carbon of the polyamine wnich contains the cheiating functionality
  • Other references to such compoun ⁇ s include Brechbiel et al , Inorg Chem 25, 2772-2781 (1986), U S Patent 4,647,447 and
  • bifunctional cheiating agents also worthy of note, consists of compounds wherein the cheiating moiety, i . e . the aminocarboxylic acid, of the molecule s attached through a nitrogen to the functional group of the molecule containing the moiety capable of reacting with tne protein
  • Mikola et al in patent application disclose a bifunctional cheiating agent prepared by reacting p- nitrobenzylbromide with DETA followed by reaction with bromoacetic acid to make the aminocarboxylic acid The nitro group is reduced to the corresponding amine group and is then converted to the isothiocyanate group by reaction with thiophosgene
  • These compounds are bifunctional chelating agents capable of chelating lanthanides which can be conjugated to bio-organic molecules for use as diagnostic agents Since attachment of the linker portion of the molecule is through one of the nitrogens of the aminocarboxylic acid, then one
  • the present invention provides a new type of a stable metal complex, especially with metals that are rare earths or pseudo-rare earths m their chemistry
  • the present invention teaches the use of these complexes and that the variance of their charge and lypophilic character may favorably alter their biodistnbution when introduced into an animal
  • the conjugates of these complexes with a biologically active material, such as an antibody, are also a part of this invention
  • These complexes and conjugates may be formulated a with suitable pharmaceutical carriers and administered to a mammal for diagnosis and/or therapy.
  • the present invention is directed to novel complexes which have a ligand that is a bicyclopolyazamacrocyclophosphonic acid compound of the formula
  • X and Y are independently H, OH, C 1 -C 3 alkyl or COOH;
  • n is an integer of 1 , 2 or 3;
  • T is H, C 1 -C 18 alkyl, COOH, OH, SO 3 H, , or
  • R 1 is -OH, C 1 -C 5 alkyl or -O-(C 1 -C 5 alkyl);
  • R 4 is H, NO 2 , NH 2 , isothiocyanato, semicarbazido, thiosemicarbazido, maleimido,
  • R 2 is H or OH; with the proviso that when R 2 is OH, then the R term containing the R 2 must have all X and Y equal to H;
  • A is CH, N, C-Br, C-CI, C-OR 3 , C-OR 8 , N + -R 5 X-, ;
  • R 3 is H, C 1 -C 5 alkyl, benzyl, or benzyl substituted with at least one R 4 ;
  • R 4 is defined as above;
  • R 5 is C 1 -C 16 alkyl, benzyl, or benzyl substituted with at least one R 4 ;
  • R 8 is C 1 -C 16 alkylamino
  • X is CI-, Br, l or H 3 CCO 2 ;
  • Q and Z independently are CH, N, N + -R 5 X; C-CH 2 -OR 3 or C-C(O)-R 6 ;
  • R 3 and R 5 are defined as above;
  • R 6 is -O-(C 1 -C 3 alkyl), OH or NHR 7 ;
  • R 7 is C 1 -C 5 alkyl or a biologically active material
  • X- is defined as above;
  • the complexes of Formula (I) use various metal ions, usually in the + 3 state, selected from: samarium ( 153 Sm), lutetium ( 177 Lu), holmium ( 166 Ho), yttrium ( 90 Y), scandium ( 47 Sc), rhenium ( 186 Re) or ( 188 Re), praseodymium ( 142 Pr), technetium ( 99m Tc), gallium ( 67 Ga) or ( 68 Ga), or indium ( 111 ln) or ( 115m In); with 153 Sm, 177 Lu, 159 Gd, 149 Pm, 140 La, 175 Yb, 166 Ho, 90 Y, 47 Sc, 142 Pr, 9 9m Tc, 67 Ga, 68 Ga, 111 ln, 113m ln or 115 m ln being preferred; with 153 Sm, 177 Lu, 166 Ho, 90 Y, 99rn Tc, 67 Ga, 6 8 Ga, 111 n,
  • Complexes having particle emissions such as 149 Pm, 142 Pr, 90 Y, or 1 75 Yb, are useful as therapeutic agents.
  • Complexes having both gamma and particle emissions such as 153 Sm, 177 Lu, 159 Gd, 140 La, 166 Ho, 47 Sc, 186 Re, 188 Re, 105 Rh, or 1 15m ln, are useful as both diagnostic and therapeutic agents.
  • the complexes so formed can be used by themselves or can be attached, by being covalently bonded, to an antibody or fragment thereof and used for diagnostic or therapeutic purposes. Such conjugates and complexes are useful as diagnostic and/or therapeutic agents.
  • X and Y are H
  • n 1 ;
  • A, Q and Z are CH.
  • Bifunctional complexes of Formula (I) are desirable to prepare the conjugates of this invention.
  • Such complexes contain a ligand which must have:
  • both T terms are P(O)R 1 OH, where R 1 is defined as above or where in the two R terms not containing an R 4 term, one T term is a COOH and the other T term is P(O)R 1 OH, where R 1 is defined as above; preferably that moiety of the above T term where one of X or Y of that term is COOH; and
  • ligands where n is 1 and/or the remaining X and Y terms are H; or
  • A is C-OR 3 or C-OR 8 , where R 3 and R 8 are defined as above or ;
  • R 4 is defined as above;
  • A is CH, and one of Q or Z is CH and the other is C-C(O)-R 6 , where R 6 is defined as above;
  • the complexes and conjugates of this invention can be designed to provide a specific overall charge which advantageously influences the in vivo biolocalization. For example, when the metal ion is + 3 the following can be obtained (A) an overall charge of -2 or more - when the metal ion is + 3 the following can be obtained (A) an overall charge of -2 or more - when the metal ion is + 3 the following can be obtained (A) an overall charge of -2 or more - when
  • T is P(O)R 1 OH, where R 1 is OH, and n is 1 ;
  • T P(O)R 1 OH, where R1 is OH, in the third R term T is COOH, and n is 1 ;
  • T is P(O)R 1 OH, where R 1 is OH
  • T is P(O)R 1 OH, where R 1 is C 1 -C 5 alkyl, and n is 1 ;
  • T is P(O)R 1 OH, where R 1 is OH
  • T is P(O)R 1 OH, where R 1 is -O-(C 1 -C 5 alkyl), and n is 1 ;
  • R term T P(O)R 1 OH, where R 1 is OH, and in the other two R terms T is
  • T in one R term T is P(O)R 1 OH, where R 1 is OH, and in the other two R terms T is P(O)R 1 OH, where R 1 is C 1 -C 5 alkyl, and n is 1 ; or
  • R term T P(O)R 1 OH, where R 1 is OH, and in the other two R terms T is COOH, and n is 1 ; or
  • T is P(O)R 1 OH, where R 1 is -O-(C 1 -C 5 alkyl), and n is 1 ; or in the three R terms T is P(O)R 1 OH, where R 1 is C 1 -C 5 alkyl, and n is 1 ; or
  • one of A, Q or Z is N + -R 5 X-, where R 5 and X- are defined as above; and in one R term, the T moiety is P(O)R 1 OH, where R 1 is C 1 -C 5 alkyl or -O-( C 1 -C 5 alkyl); and in the other two R terms, the T moiety is COOH or P(O)R 1 OH, where R 1 is C 1 -C 5 alkyl or -O-(C 1 -C 5 alkyl); and all X and Y terms are H.
  • Both the complexes and conjugates may be formulated to be in a
  • the complexes of this invention contain a ligand of Formula (I) which is numbered for nomenclature purposes as follows:
  • the present invention concerns development of radiopharmaceutical agents having synthetic modifications to the chelate enabling site specific delivery of the
  • the advantage being an increased delivery of the radiopharmaceutical agent in the areas of interest based upon tissue affinity
  • the specificity of the complex of Formula (I) may be controlled by adjusting the total charge and lipophilic character of the complex
  • the overall range of the charge of the complex is from -3 to + 1
  • the overall charge is highly negative and bone uptake is expected, whereas when the overall charge of the complex is O (thus neutral), the complex may have the ability to cross the blood brain barrier and normal brain uptake may be possible
  • Tissue specificity may also be realized by ionic or covalent attachment of the chelate to a naturally occurring or synthetic molecule having specificity for a desired target tissue
  • ionic or covalent attachment of the chelate to a naturally occurring or synthetic molecule having specificity for a desired target tissue
  • radiopharmaceutical agents of Formula (I) which are neutral in charge are particularly preferred for forming the conjugates of this invention since undesirable ionic interactions between the chelate and protein are minimized which preserves the antibody imr ⁇ unoreactivity
  • C 1 -C 3 alkyl includes both straight and branched chain alkyl groups
  • Antibody refers to any polyclonal, monoclonal, chimeric antibody or heteroantibody, preferably a monoclonal antibody; "antibody fragment” includes Fab fragments and F(ab') 2 fragments, and any portion of an antibody having specificity toward a desired epitope or epitopes.
  • antibody fragment includes Fab fragments and F(ab') 2 fragments, and any portion of an antibody having specificity toward a desired epitope or epitopes.
  • Preferred antibodies are 1 116-NS-19-9 (anti-colorectal carcinoma), 1 1 16-NS-3d (anti-CEA), 703D4 (anti-human lung cancer), 704A1 (anti-human lung cancer), CC49 (anti-TAG-72), CC83 (anti-TAG-72) and B72.3.
  • the hybridoma cell lines 1116-NS-19-9, 1116-NS-3d, 703D4, 704A1 , CC49, CC83 and B72.3 are deposited with the American Type Culture Collection, having the accession numbers ATCC HB 8059, ATCC CRL 8019, ATCC HB 8301 , ATCC HB 8302, ATCC HB 9459, ATCC HB 9453 and ATCC HB 8108, respectively.
  • complex refers to a complex of the compound of the invention, e.g. Formula (I), complexed with a metal ion, where at least one metal atom is chelated or sequestered;
  • conjugate refers to a metal ion conjugate that is covalently attached to an antibody or antibody fragment.
  • bifunctional coordinator e.g., bifunctional cheiating agent
  • functionalized chelant are used interchangeably and refer to com pounds that have a chelant moiety capable of cheiating a metal ion and a moiety covalently bonded to the chelant moiety that is capable of serving as a means to covalently attach to an antibody or antibody fragment.
  • the bifunctional cheiating agents described herein can be used to chelate or sequester the metal ions so as to form metal ion chelates (also referred to herein as "complexes").
  • the complexes because of the presence of the functionalizing moiety (represented by R 4 or R 8 in Formula I), can be covalently attached to biologically active materials, such as dextran, molecules that have specific affinity for a receptor, or preferably covalently attached to antibodies or antibody fragments.
  • biologically active materials such as dextran, molecules that have specific affinity for a receptor, or preferably covalently attached to antibodies or antibody fragments.
  • conjugates are referred to herein as "conjugates”.
  • salts means any salt or mixtures of salts of a complex or conjugate of formula (I) which is sufficiently non-toxic to be useful in therapy or diagnosis of animals, preferably mammals. Thus, the salts are useful in accordance with this invention.
  • salts formed by standard reactions from both organic and inorganic sources include, for example, sulfuric, hydrochloric, phosphoric, acetic, succinic, citric, lactic, maleic, fumaric, palmitic, cholic, palmoic, mucic, glutamic, gluconic, d-camphoric, glutaric, glycolic, phthalic, tartaric, formic, lauric, steric, salicylic, methanesulfonic, benzenesulfonic, sorbic, picric, benzoic and cinnamic acids and other suitable acids.
  • salts formed by standard reactions from both organic and inorganic sources such as ammonium, alkali metal ions, alkaline earth metal ions, and other similar ions. Particularly preferred are the salts of the complexes or conjugates of formula (I) where the salt is potassium, sodium or ammonium. Also included are mixtures of the above salts.
  • the ligands for use in the complex or conjugate of Formula (I) are prepared by various processes. Typical general synthetic approaches to such processes are provided by the reaction schemes given below.
  • R 1 C 1 -C 5 alkyl
  • Q, A and Z CH.
  • R 1 -O-(C 1 -C 5 alkyl) or C 1 -C 5 alkyl;
  • R 1 -O-(C 1 -C 5 alkyl) or C 1 -C 5 alkyl;
  • R 4 H, NO 2 , NH 2 or SCN
  • R 1 -O-(C 1 -C 5 alkyl) or C 1 -C 5 alkyl;
  • R 1 -OH, -O-(C 1 -C 5 alkyl) or C 1 -C 5 alkyl;
  • R 1 -OH, -O-(C 1 -C 5 alkyl) or C 1 -C 5 alkyl;
  • R 1 -OH, -O-(C 1 -C 5 alkyl) orC 1 -C 5 alkyl;
  • R 1 -OH, -O-(C 1 -C 5 alkyl) or C 1 -C 5 alkyl;
  • R 1 -OH, -O-(C 1 -C 5 alkyl) or C 1 -C 5 alkyl;
  • the synthetic Scheme 1 begins with a halogenation of commercially available bispyridyl alcohol (1) using thionyl chloride. Similar procedures for converting an alcohol to an electrophilic substrate, such as treatment with toluenesulfonyl chloride, HBr or HCl, should also result in a similarly reactive product which would work well in subsequent ring closure reactions. Macrocyclization procedures are numerous in the literature and the desired tetraazamacrocycle (3) was prepared according to the method of Stetter et al., Tetrahedron 37, 767-772 (1981). More general procedures have since been published which give good yields of similar macrocycles using milder conditions [A. D. Sherry et al., J. Org. Chem.
  • phosphonate esters [e.g. of formula (6)] can also be prepared under organic conditions in alcohols or aprotic solvents (e.g.
  • Esters of this type are also prepared via N-alkylation of ⁇ -halodialkylphosphonates in solvents such as acetonitrile, chloroform, dimethylformamide, tetrahydrofuran or 1 ,4-dioxane with or without the addition of a non-nucleophilic base such as potassium carbonate at room temperature or above.
  • solvents such as acetonitrile, chloroform, dimethylformamide, tetrahydrofuran or 1 ,4-dioxane
  • a non-nucleophilic base such as potassium carbonate at room temperature or above.
  • macrocyclic methylphosphinic acids (10 and 1 1) are prepared under conditions similar to those described in Scheme 2.
  • condensation can be conducted in solvents such as tetrahydrofuran, dimethylformamide, dioxane, acetonitrile or alcholic media.
  • the resulting phosphinate ester is then hydrolyzed under acid (6N HCl, 80-100°C) or basic (stoichiometric quantities of base, 40-100°C) conditions to give the corresponding methylphosphonic acid.
  • the method devised by A. D. Sherry et al. (Inorg. Chem., submitted 1991 ) using ethyl phosphonic acid generated in situ can be used to obtain phosphinate derivatives having increased lipophilic character.
  • Scheme 4 illustrates an approach to incorporate additional functionality into the pyridine unit of the 12-membered tetraazamacrocycle.
  • chelidamic acid Sigma Chemical Company; 12
  • the bis-halomethyl derivative (13) having appropriate substitution at the pyridyl 4-position. Transformations leading to this intermediate are general in nature and its preparation is described by Takalo et al. [Acta Chemica Scandinavica B 42, 373-377 (1988)].
  • Subsequent macrocyclization using this intermediate (15) can be accomplished by the standard DMF reaction at 100°Cwith the sodiotritosylated triamine, or at room
  • organometallic Pd(II) complexes can be employed to facilitate the coupling reaction between phenylacetylene and phenylacetylene derivatives and the pyridyl macrocycle.
  • Typical reaction conditions for this transformation utilize anhydrous conditions with triethylamine as solvent and at reaction temperature between about 10 to about 30°C for optimum yields.
  • the identical product can also be obtained using Cu(l) phenylacetylide in anhydrous pyridine at a
  • 4-hydroxypyridyl moiety (29) is alkylated with a bromoalkylnitrile yielding an intermediate ether linked nitrile (31 ) which is subsequently incorporated into the macrocyclic structure.
  • This type of alkylation procedure is best accomplished under anhydrous conditions in an aprotic solvent such as tetrahydrofuran (THF) and using a non-nucleophilic base such as sodium hydride or butyl lithium at temperatures between from about -30 to about 80°C.
  • THF tetrahydrofuran
  • a non-nucleophilic base such as sodium hydride or butyl lithium
  • the macrocyclic nitrile prepared in this manner can be reduced to the primary amine (36) by standard procedures foil owed by protection of the primary amine with 2-(t-butoxycarbonyloxyimino)-2-phenylacetonitrile (BOC-ON; 37) .
  • BOC-ON 2-(t-butoxycarbonyloxyimino)-2-phenylacetonitrile
  • Subsequent functionalization of the macrocyclic secondary amines 38, 39, 40, 41 , 42, 43
  • the tris-tosylated macrocycle intermediate (46) can be detosyiated under acidic conditions (HBr/AcOH, 25-1 15°C) with simultaneous hydrolysis to yield the nicotinic acid derivative (48), or reduction of the ester in refluxing ethanol prior to detosyiation will result in the 3-hydroxymethyl intermediate (47).
  • the nicotinic acid macrocycle can then be substituted into the general scheme for secondary amine functionalization to yield the various types of phosphonate cheiants of Formula (I) (49, 50, 51 , 52, 53).
  • the 3-hydroxymethyl analog is advantageously protected prior to functionalization of the macrocyclic amines.
  • the benzyl (Bz) protecting group is shown in Scheme 8 since it must be resistant to the severe acid conditions encountered in the detosyiation step. After appropriate functionalization of the secondary amines has been accomplished as described in previous Schemes, the benzyl group is removed under mild catalytic hydrogenation conditions (58).
  • Macrocyclic derivatives can also be prepared as in Schemes 12- 14 where both carboxylate and phosphonate cheiating fuctionalities are present in the same molecule.
  • carboxylate functionality can be introduced under typical aqueous alkylation procedures using bromoacetic acid.
  • the remaining amines can be phosphonomethylated by procedures discussed in previous Schemes using formaldehyde and phosphorous acid, diaikyl phosphonates or trialkyl phosphites.
  • Schemes 15 and 16 delineate a synthetic approach which introduces an aromatic nitrobenzyl substituent at one of the macrocyclic nitrogen positions.
  • the macrocyclic amine is mono-N-functionalized in an organic solvent such as acetonitrile or DMF at room temperature using a non-nucleophilic base such as potassium carbonate. Additional functionalization of the remaining nitrogen positions is then preformed by methods and conditions described in previous Schemes.
  • the nitro group is reduced using platinum oxide and hydrogen in water.
  • the cheiating agent is compatible with conjugation techniques which will enable attachment to larger synthetic or natural molecules.
  • the metal ions used to form the complexes of this invention are 153 Sm, 177 Lu, 159 Gd, 149 Pm, 140 La, 175 Yb, 166 Ho, 90 Y, 47 Sc, 186 Re, 188 Re, 142 Pr, 99m Tc, 67 Ga, 68 Ga, 105 Rh, 97 Ru, 1 11 In, 113m In or 115m ln.
  • the anion present is halide, preferably chloride, or salt free (metal oxide).
  • the complexes are prepared by methods well known in the art Thus, for example, see Chelating Agents and Metal Chelates, Dwyer & Mellor, Academic Press (1964), Chapter 7 See also methods for making ammo acids in Synthetic Production and Utilization of Ammo Acids, (edited by Kameko, et al ) John Wiley & Sons (1974)
  • An example of the preparation of a complex involves reacting a bicyclopolyazamacrocyclophosphonic acid with the metal ion under aqueous conditions at a pH from 5 to 7
  • the complex formed is by a chemical bond and results in a stable radionuclide composition, e g stable to the disassociation of the radionuclide from the ligand
  • the complexes of the present invention are administered at a ligand to metal molar ratio of at least about 1 : 1 , preferably from 1 : 1 to 3: 1 , more preferably from 1 : 1 to 1 5: 1
  • a large excess of ligand is undesirable since uncomplexed ligand may be toxic to the animal or may result in cardiac arrest or hypocalcemic convulsions
  • antibodies or antibody fragments which may be used in the conjugates described herein can be prepared by techniques well known in the art Highly specific monoclonal antibodies can be produced by hybridization techniques well known in the art, see for example, Kohler and Milstein [Nature, 256, 495-497 (1975); and Eur J Immunol , 6, 511-519 (1976)] Such antibodies normally have a highly specific reactivity
  • antibodies directed against any desired antigen or hapten may be used
  • the antibodies which are used in the conjugates are monoclonal antibodies, or fragments thereof having high specificity for a desired epitope(s)
  • Antibodies used in the present invention may be directed against, for example, tumors, bacteria, fungi, viruses, parasites, mycoplasma, differentiation and other cell membrane antigens, pathogen surface antigens, toxins, enzymes, allergens, drugs and any biologically active molecules
  • Some examples of antibodies or antibody fragments are 1 1 16-NS-19-9, 1 1 16-NS-3d, 703D
  • compositions may be in the form of a suspension, injectable solution or other suitable formulations
  • Physiologically acceptable suspending media, with or without adjuvants may be used
  • an "effective amount" of the formulation is used for diagnosis and therapy
  • the dose will vary depending on the disease and physical parameters of the animal, such as weight
  • In vivo diagnostics are also contemplated using formulations of this invention
  • ICP inductively coupled plasma
  • ⁇ L microliter(s).
  • a stock 153 SmCI 3 solution was prepared by adding 2 ⁇ L of 3 ⁇ 10 -4 M 153 SmCI 3 in 0.1 N HCl to 2 mL of a 3 ⁇ 10 -4 M SmCl 3 carrier solution.
  • Appropriate ligand solutions were then prepared in deionized water.
  • the percent metal as a complex was then determined by passing a sample of the complex solution through a SephadexTM G-50 column, eluting with 4: 1 saline (85% NaCI/NH 4 OH) and collecting 2 ⁇ 3 mLfractions. The amount of radioactivity in the combined elutions was then compared with that left on the resin (non-complexed metal is retained on the resin).
  • the pH stability profile was generated by adjusting the pH of an aliquot of the complex solution using 1M NaOH or 1M HCl and determining the percent of the metal existing as a complex using the ion exchange method described above. STARTING MATERIALS
  • a solution of HBr and AcOH was prepared by mixing 48% HBr and glacial AcOH in a 64:35 ratio.
  • To 1 12 mL of the HBr/AcOH mixture was added 5.5 g (8.2 mmol) of 3,6,9-tris(p-tolylsulfonyl)-3,6,9,15-tetraazabicyclo[9.3.1]pentadeca-1 (15),1 1 ,13-triene (prepared by the procedure of Example B) and the reaction mixture was heated at mild reflux with constant stirring for 72 hrs. The reaction mixture was then cooled to room temperature and
  • a 1 : 1 ligand/metal complex was then prepared by combining 40 ⁇ l of the ligand solution with 2 mL of aqueous SmCI 3 -H 2 O (3 ⁇ 10 -4 M in 0.1 N HCl) containing tracer 153 SmCI 3 .
  • the percent metal as a complex was determined by passing a sample of the complex solution through a SephadexTM column, eluting with 4: 1 saline (0.85% NaCI/NH 4 OH), and collecting 2 ⁇ 3 mL fractions.
  • the percent dose in blood was estimated assuming blood to be 7% of the body weight.
  • the percent dose in bone was estimated by multiplying the percent dose in the femur by 25.
  • the percent dose in muscle was estimated assuming muscle to be 43% of the body weight.
  • the percent of the injected dose of complex of of of Example 2 ( 153 Sm-PCTMP) in several tissues are given in Table I.
  • the numbers represent the average of 5 rats per data point.
  • the percent of the injected dose of complex of 90 Y with the ligand of Example 1 (PCTMP), prepared in Example 4, in several tissues are given in Table III.
  • the numbers represent the average of 3 rats er data oint.
  • the bone to blood ratio (% dose/G) was 140.
  • the bone to liver ratio was 76.
  • the bone to muscle ratio was 400.

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Abstract

Complexes de composés d'acides bicyclopolyazamacrocyclophosphoniques comprenant un ion métal tel que ?153Sm, 177Lu, 159Gd, 149Pm, 140La, 175Yb, 166Ho, 90Y, 47Sc, 186Re, 188Re, 142Pr, 99mTc, 67Ga, 68Ga, 105Rh, 97Ru, 111In, 113mIn ou 115m¿In. Les complexes peuvent être liés par covalence à une molécule biologiquement active telle qu'un anticorps ou un fragment d'anticorps pour former des conjugués. Les complexes et les conjugués sont utiles comme agents radiopharmaceutiques dans des applications de thérapie et/ou de diagnostic. Des procédés de préparation du complexe et du conjugué sont également présentés.
PCT/US1993/004356 1993-05-06 1993-05-06 Complexes d'acides bicyclopolyazamacrocyclophosphoniques, conjugues de ces derniers, procede de preparation associe et d'utilisation en tant que produits radiopharmaceutiques WO1994026755A1 (fr)

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PCT/US1993/004356 WO1994026755A1 (fr) 1993-05-06 1993-05-06 Complexes d'acides bicyclopolyazamacrocyclophosphoniques, conjugues de ces derniers, procede de preparation associe et d'utilisation en tant que produits radiopharmaceutiques
AU42398/93A AU4239893A (en) 1993-05-06 1993-05-06 Bicyclopolyazamacrocyclophosphonic acid complexes, a process for their preparation, and their conjugates, for use as radiopharmaceuticals

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997040055A1 (fr) * 1996-04-19 1997-10-30 The Dow Chemical Company Chelates fluorescents utilises en tant qu'agents visuels destines a l'imagerie et specifiques de certains tissus
EP0817787A1 (fr) * 1995-03-27 1998-01-14 Isis Pharmaceuticals, Inc. Composes macrocycliques azotes
WO2014030993A1 (fr) * 2012-07-18 2014-02-27 Universiti Malaya (Um) Microsphères marquées au 153sm et activées par des neutrons

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1990002571A1 (fr) * 1988-09-16 1990-03-22 Cis Bio International Produits radiopharmaceutiques constitues par des complexes tetraphosphonates
EP0391766A1 (fr) * 1989-03-24 1990-10-10 Guerbet S.A. Nouveaux ligands macrocycliques azotés, procédé de préparation, complexes métalliques formés par ces ligands, composition de diagnostic et composition thérapeutique les contenant
WO1991010669A1 (fr) * 1990-01-19 1991-07-25 Cockbain, Julian, Roderick, Michaelson Composes de chelation
WO1991010645A2 (fr) * 1990-01-19 1991-07-25 Cockbain, Julian, Roderick, Michaelson Agents de chelation
WO1993011801A1 (fr) * 1991-12-10 1993-06-24 The Dow Chemical Company Complexes d'acides bicyclopolyazamacrocyclophosphoniques, leur preparation, conjugues et agents radiopharmaceutiques

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1990002571A1 (fr) * 1988-09-16 1990-03-22 Cis Bio International Produits radiopharmaceutiques constitues par des complexes tetraphosphonates
EP0391766A1 (fr) * 1989-03-24 1990-10-10 Guerbet S.A. Nouveaux ligands macrocycliques azotés, procédé de préparation, complexes métalliques formés par ces ligands, composition de diagnostic et composition thérapeutique les contenant
WO1991010669A1 (fr) * 1990-01-19 1991-07-25 Cockbain, Julian, Roderick, Michaelson Composes de chelation
WO1991010645A2 (fr) * 1990-01-19 1991-07-25 Cockbain, Julian, Roderick, Michaelson Agents de chelation
WO1993011801A1 (fr) * 1991-12-10 1993-06-24 The Dow Chemical Company Complexes d'acides bicyclopolyazamacrocyclophosphoniques, leur preparation, conjugues et agents radiopharmaceutiques

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0817787A1 (fr) * 1995-03-27 1998-01-14 Isis Pharmaceuticals, Inc. Composes macrocycliques azotes
EP0817787A4 (fr) * 1995-03-27 2000-09-13 Isis Pharmaceuticals Inc Composes macrocycliques azotes
WO1997040055A1 (fr) * 1996-04-19 1997-10-30 The Dow Chemical Company Chelates fluorescents utilises en tant qu'agents visuels destines a l'imagerie et specifiques de certains tissus
AU719002B2 (en) * 1996-04-19 2000-05-04 Dow Chemical Company, The Fluorescent chelates as visual tissue specific imaging agents
WO2014030993A1 (fr) * 2012-07-18 2014-02-27 Universiti Malaya (Um) Microsphères marquées au 153sm et activées par des neutrons

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