BICYCLOPOLYAZAMACROCYCLOPHOSPHONIC ACIDS, THEIR COMPLEXES AND CONJUGATES, FOR USE AS CONTRAST AGENTS, AND PROCESSES FOR THEIR PREPARATION

Abstract: Bicyclopolyazamacrocyclophosphonic acid compounds are disclosed which may form inert complexes with Gd, Mn or Fe ions. The overall charge of the complex can be varied to alter the in vivo biolocalization. Such complexes can be covalently attached to an antibody, antibody fragment or other biologically active molecule to form conjugates. The complexes and conjugates are useful as contrast agents for diagnostic purposes. Processes for the preparation of the ligand, complex and conjugate are also disclosed.

Description: BICYCLOPOLYAZAMACROCYCLOPHOSPHONIC ACIDS, THEIR COMPLEXES AND CONJUGATES, FOR USE AS CONTRAST AGENTS, AND PROCESSES FOR THEIR PREPARATION This invention concerns I igands that are bicyclopolyazamacrocyclophosphonic acids, and complexes and conjugates thereof, for use as contrast agents in magnetic resonance imaging (MRI). Some ligands and complexes are also useful as oral care agents and as scale inhibiting agents in water treatment systems. To better understand this invention, a brief background on MRI is provided in the following section. Background MRI is a non-invasive diagnostic technique which produces well resolved cross- sectional images of soft tissue within an animal body, preferably a human body. This technique is based upon the property of certain atomic nuclei (e.g. water protons) which possess a magnetic moment [as defined by mathematical equations; see G. M. Barrow, Physical Chemistry, 3rd Ed., McGraw-Hill, NY (1973)] to align in an applied magnetic field. Once aligned, this equilibrium state can be perturbed by applying an external radio frequency (RF) pulse which causes the protons to be tilted out of alignment with the magnetic field. When the RF pulse is terminated, the nuclei return to their equilibrium state and the time required for this to occur is known as the relaxation time. The relaxation time consists of two parameters known as spin-lattice (T1) and spin-spin (T2) relaxation and it is these relaxation measurements which give information on the degree of molecular organization and interaction of protons with the surrounding environment. Since the water content of living tissue is substantial and variations in content and environment exist among tissue types, diagnostic images of biological organisms are obtained which reflect proton density and relaxation times. The greater the differences in relaxation times (T1 and T2) of protons present in tissue being examined, the greater will be the contrast in the obtained image [J. Magnetic Resonance 33, 83-106 (1979)]. It is known that paramagnetic chelates possessing a symmetric electronic ground state can dramatically affect the T1 and T2 relaxation rates of juxtaposed water protons and that the effectiveness of the chelate in this regard is related, in part, to the number of unpaired electrons producing the magnetic moment [Magnetic Resonance Annual , 231-266, Raven Press, NY (1985)]. It has also been shown that when a paramagnetic chelate of this type is administered to a living animal, its effect on the T1 and T2 of various tissues can be directly observed in the magnetic resonance (MR) images with increased contrast being observed in the areas of chelate localization. It has therefore been proposed that stable, non-toxic paramagnetic chelates be administered to animals in order to increase the diagnostic information obtained by MRI [Frontiers of Biol. Energetics I, 752-759 (1978); J. Nucl. Med. 25, 506-513 (1984); Proc. of NMR Imaging Syrnp. (Oct. 26-27, 1980); F. A. Cotton et a I., Adv. Inorg. Chem. 634-639 (1966)]. Paramagnetic metal chelates used in this manner are referred to as contrast enhancement agents or contrast agents. There are a number of paramagnetic metal ions which can be considered when undertaking the design of an MRI contrast agent. In practice, however, the most useful paramagnetic metal ions are gadolinium (Gd +3 ), iron (Fe +3 ), manganese (Mn +2 ) and (Mn + 3 ), and chromium (Cr* 3 ), because these ions exert the greatest effect on water protons by virtue of their large magnetic moments. In a non-complexed form (e.g. GdCi , these metal ions are toxic to an animal, thereby precluding their use in the simple salt form. Therefore, a fundamental role of the organic chelating agent (also referred to as a ligand) is to render the paramagnetic metal non-toxic to the animal while preserving its desirable influence on T1 and T2 relaxation rates of the surrounding water protons. Art in the MRI field is quite extensive, such that the following summary, not intended to be exhaustive, is provided only as a review of this area and other compounds that are possibly similar in structure. U.S. Patent 4,899,755 discloses a method of alternating the proton NMR relaxation times in the liver or bile duct of an animal using Fe +3 -ethylene-bis(2- hydroxyphenylglycine) complexes and its derivatives, and suggests among various other compounds the possible use of a pyridine macrocyclomethylenecarboxylic acid. U.S. Patent 4,880,008 (a CIP of U.S. Patent 4,899,755) discloses additional imaging data for liver tissue of rats, but without any additional complexes being shown. U.S. Patent 4,980,148 disclose gadolinium complexes for MRI which are non-cyclic compounds. C. J. Broan et al., 7. Chem. Soc, Chem. Commun., 1739-1741 (1990) describe some bifunctional macrocyclic phosphinic acid compounds. C. J. Broan et al., 7. Chem. Soc, Chem. Commun., 1738-1739 (1990) describe compounds that are triazabicyclo compounds. I. K. Adzamli et al., . Med. Chem. 32, 139-144 (1989) describes acyclic phosphonate derivatives of gadolinium complexes for NMR imaging. At the present time, the only commercial contrast agents available in the U.S.A. are the complex of gadolinium with diethylenetriaminepentaacetic acid (DTPA-Gd + 3 - MAGNEVIST * " by Schering AG) and a D03A derivative [1 , 4,7-tris(carboxymethyl)-10-(2- hydroxypropyl)-1 , 4,7,10-tetraazacyclododecanato]gadolinium (PROHANCE™ by Squibb). MAGNEVIST™ and PROHANCE'" are each considered as a non-specific perfusion agent since it freely distributes in extracellular fluid followed by efficient elimination through the renal system. MAGNEVIST'" has proven to be extremely valuable in the diagnosis of brain lesions since the accompanying breakdown of the blood/brain barrier allows perfusion of the contrast agent into the affected regions. In addition to MAGNEVIST'", Guerbet is commercially marketing a macrocyclic perfusion agent (DOTAREM™) which presently is only available in Europe. PROHANCE™ is shown to have fewer side effects than Magnevist". A number of other potential contrast agents are in various stages of development. Surprisingly, it has now been found that various bicyclopolyazamacrocyclo- phosphonic acid ligands can be contrast agents. Furthermore, these ligands may have their charge modified, i.e. bythe structure of the ligand and metal selected, which can effect their ability to be more site specific. Specifically, the present invention is directed to novel ligands that are bicyciopolyazamacrocyclophosphonic acid compounds of the formula R-N N-R wherein: f R = " ( C ) n -T ; I Y where: X and Y are independently H, OH, C.-C. alkyl or COOH; n is an integer of 1 , 2 or 3; with the proviso that: when n is 2, then the sum of X and Y must equal two or more H; and when n is 3, then the sum of X and Y must equal three or more H; T is H, C C 18 alkyl, COOH, OH, S0 3 H, where: RJs OH, C.-C 5 alkyl or -0-(C.-C 5 alkyl); R 4 is H, N0 2 , NH 2 , isothiocyanato, semicarbazido, thiosemicarbazido, maleimido, bromoacetamido or carboxyl ; 2 is H or OH; with the proviso that when R 2 is OH, then the Rterm containing the R 2 must have all X and Y equal to H; with the proviso that at least one T must be P(0)R'OH, and with the proviso that when one T is then one X or Y of that R term may be COOH and all other X and Y terms of that Rterm must be H; A is CH, N, C-Br, C-CI, C-OR 3 , C-OR 8 , N + -R 5 X " , R 3 is H, C.-C 5 alkyl, benzyl, or benzyl substituted with at least one R 4 ; R 4 is def i ned as above; R 5 is C^C^ alkyl, benzyl, or benzyl substituted with at least one R 4 ; R 8 is C.-C ]6 alkylamino; X is CI , Br J or H 3 CC0 2 -; Q and Z independently are CH, N, N + -R 5 X " , C-CH 2 -OR 3 or C-C(0)-R 5 ; R s is defined as above; R 6 is -0-(C 1 -C 3 alkyl), OH or NHR 7 ; R 7 is C.-C 5 alkyl or a biologically active material; X " is defined as above; or pharmaceutically-acceptable salts thereof; with the proviso that: a) when Q, A or Z is N or N + -R 5 X ' , then the other two groups must be CH; b) when A is C-Br, C-CI, C-OR 3 or C-OR 8 , then both Q and Z must be CH; c) the sum of the R 4 , R 7 and R 8 terms, when present, may not exceed one; and d) only one of Q or Z can be C-C(0)-R 6 and when one of Q or Z is C-C(0)-R 6 , then A must be CH. When the above ligands of Formula (I) have at least two of the R terms T equal to P0 3 H 2 [P(0)R'OH where i is OH] and the third T equal H, COOH or C.-C,, alkyl; A, Q and Z are CH; n is 1 ; and X and Y independently are H or C.-C 3 alkyl; then the ligands are useful for oral care. Particularly preferred are those ligands where in the three R terms T is P(0)R 1 OH, where R 1 is OH; n is 1 ; and X and Y are H. The use of these ligands is discussed and claimed in other copending applications. When the above ligands of Formula (I) have: in the Rterm at least two T equal PfOJR'OH, where R' is OH, and in the other R term, T is COOH or PfO^OH, and n, R\ X, Y, A, Q and Z are defined as above; in at least one R term T is P(0)R'OH, where R 1 is OH, and in the other two R terms, T is COOH or P(0)R 1 OH, and n, R X, Y, A, Q and Z are defined as above; or in the R term three T equal P(0)R'OH, where R' is C.-C 5 alkyl or -0-(C.-C 5 alkyl), and n, R 1 , X, Y, A, Q and Z are defined as above; then the ligands are useful as contrast agents. Particularly preferred are those ligands of Formula (I) where: X and Y are H; n is 1 ; or A, Q and Zare CH. Preferrably the ligands and complexes of Formula (I) do not have all three T equal to PO3H2 [P(0)R'OH where Ri is OH] when A, Q and Z are CH; although such complexes are useful as contrast agents or oral care agents. Thus the ligands and complexes of Formula (I) may have a proviso that not all T may be equal to P0 3 H [P(0)R'OH where R i is OH] when A, Q and Z are CH, unless used as a contrast agent or oral care agent. Bifunctional ligands of Formula (I) are desirable to prepare the conjugates of this invention. Such ligands must have: one R term where the T moiety is where R 2 and R 4 are defined as above, especially where in the two R terms not containing an R 4 term, both T terms are P(0)R'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(0)R'OH, where R 1 is defined as above; preferrably that moiety of the above T term where one of X or Y of that term is COOH; and also preferred are those 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 R8 are defined as above or where R 4 is defined as above; or A is CH, and one of Q or Z is CH and the other is C-C(0)-R 6 , where R 6 is defined as above; especially those ligands where R 6 is NHR 7 , where R 7 is a biologically active material The ligands of Formula (I) may be complexed with various metal ions, such as gadolinium (Gd + 3 ), iron (Fe * 3 ), and manganese (Mn +2 ), with Gd *3 being preferred. The complexes so formed can be used by themselves or can be attached, by being covalently bonded to a larger molecule such as a dextran, a polypeptide or a biologically active molecule, including an antibody or fragment thereof, and used for diagnostic purposes. Such conjugates and complexes are useful as contrast agents. The complexes and conjugates of Formula (I) can be designed to provide a specific overall charge which advantageously influences the in vivo biolocalization and image contrast. For example, when the metal ion is + 3 the following can be obtained: (A) an overall charge of -2 or more -when in three R terms T is P(0)R'OH, where R 1 is OH, and n is 1 ; or in two R terms T is P(0)R'OH, where R 1 is OH, in the third R term T is COOH, and n is 1 ; or in two R terms T is P(0)R'OH, where R 1 is OH, in the third R term T is P(0)R 1 OH, where R 1 is C„-C 5 alkyl, and n is 1 ; or in two R terms T is P(0)R 1 OH, where R 1 is OH, in the third R term T is P(0)R'OH, where R 1 is -0-(C.-C 3 alkyl), and n is 1; or (B) an overall charge of -1 - when in one R term T is P(0)R'OH, where R' is OH, and in the other two R terms T is P(0)R 1 OH, where R' is -0-(C.-C 3 alkyl), and n is 1 ; or in one R term T is P(0)R'OH, where R 1 is OH, and in the othertwo R terms T is P(0)R 1 OH, where R' is C,-C 5 alkyl, and n is 1 ; or in one R term T is PfOJR'OH, where R 1 is OH, and in the othertwo R terms T is COOH, and n is 1 ; or (C) an overall neutral charge - when in the three R terms T is P(0)R 1 OH, where R 1 is -0-(C.-C 5 alkyl), and n is 1 ; or in the three R terms T is P(0)R 1 OH, where R 1 is C.-C 5 alkyl, and n is 1 ; or (D) an overall charge of + 1 - when 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(0)R 1 OH, where R 1 is C^Q. alkyl or -0-(C.-C 5 alkyl); and in the other two R terms, the T moiety is COOH or P(0)R'OH, where R 1 is C.-C 5 alkyl, -0-(C.-C 5 alkyl); and all X and Y terms are H. Both the complexes and conjugates may be formulated to be in a pharmaceutically acceptable form for administration to an animal. Use of the ligands of Formula (I) with other metal ions for diagnosis of disease states such as cancer is possible. The compounds of Formula (I) are numbered for nomenclature purposes as follows: One aspect of the present invention concerns development of contrast agents having synthetic modifications to the paramagnetic chelate enabling site specific delivery of the contrast agent to a desired tissue. The advantage being increased contrast in the areas of interest based upon tissue affinity as opposed to contrast arising from non-specific perfusion which may or may not be apparent with an extracellular agent. The specificity of the ligand 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. For example, for a complex having 2 or more P0 3 H 2 groups, the overall charge is highly negative and bone uptake is expected; whereas when the overall charge of the complex is 0 (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. One possible application of this approach is through the use of chelate conjugated monoclonal antibodies which would transport the paramagnetic chelate to diseased tissue enabling visualization by MRI. In addition, attachment of a paramagnetic chelate to a macromolecule can further increase the contrast agent efficiency resulting in improved contrast relative to the unbound chelate. Recent work by Lauffer (U.S. Patents 4,880,008 and 4,899,755) has demonstrated that variations in lipophilicity can result in tissue-specific agents and that increased iipophilic character favors non-covalent interactions with blood proteins resulting in enhancement of relaxivity. Additionally, the present contrast 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 immunoreactivity. Also the present neutral complexes reduce the osmolarity relative to DTPA- Gd +3 , which may alleviate the discomfort of injection. While not wishing to be bound by theory, it is believed that when a charged complex of the invention is made (e.g. possibly -2 or -3 for bone, -1 for liver, or + 1 for heart), the variations in that chelate ionic charge can influence biolocalization. Thus, if the antibody or other directing moiety is also specific for the same site, then the conjugate displays two portions to aid in site specific delivery. The terms used in Formula (I) are further defined as follows. "C.-C 3 alkyl", "C.-C 5 alkyl", "C.-C alkyl", include both straight and branched chain alkyl groups. An "animal" includes a warmblooded mammal, preferably a human being. "Biologically active material" refers to a dextran, peptide, or molecules that have specific affinity for a receptor, or preferably antibodies or antibody fragments. "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. When using the term "radioactive metal chelate/antibody conjugate" or "conjugate", the "antibody" is meant to include whole antibodies and/or antibody fragments, including semisynthetic or genetically engineered variants thereof. Possible antibodies are 1 1 16-NS-19-9 (anti-col orectal carcinoma), 1 116-NS-3d (anti-CEA), 703D4 o (anti-human lung cancer), 704A1 (anti-human lung cancer), CC49 (anti-TAG-72), CC83 (anti- TAG-72) and B72.3. The hybridoma cell lines 1 1 16-NS-19-9, 1 1 16-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. 5 As used herein, "complex" refers to a complex of the compound of Formula (I) complexed with a metal ion, where at least one metal atom is chelated or sequestered; "conjugate" refers to a metal ion chelate that is covalently attached to an antibody or antibody fragment. The terms "bifunctional coordinator", "bifunctional chelating agent" and "functionalized chelant" are used interchangeably and refer to compoundsthat have a chelant 0 moiety capable of chelating 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 chelating agents described herein (represented by Formula I) 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 5 (represented by R 4 or R8 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. Thus the complexes described herein may be covalently attached to an antibody or antibody fragment or have specific affinity for a receptor and are referred to herein as "conjugates". 0 As used herein, "pharmaceutically-acceptable salts" means any salt or mixtures of salts of a compound 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. Representative of those salts formed by standard reactions from both organic and inorganic sources include, for example, sulfuric, hydrochloric, phosphoric, acetic, succinic, citric, 5 lactic, maleic, fumaric, palmitic, cholic, palmoic, mucic, glutamic, gluconic acid, d-camphoric, glutaric, glycolic, phthalic, tartaric, formic, lauric, steric, salicylic, methanesulfonic, benzenesulfonic, sorbic, picric, benzoic, cinnamic acids and other suitable acids. Also included are salts formed by standard reactions from both organic and inorganic sources such as ammonium or 1-deoxy-1-(methylamino)-D-glucitol, alkali metal ions, alkaline earth metal ions, and other similar ions. Particularly preferred are the salts of the compounds of Formula (I) where the salt is potassium, sodium, ammonium. Also included are mixtures of the above salts. Detailed Description of the Process The compounds of Formula (I) are prepared by various processes. Typical general synthetic approaches to such processes are provided by the reaction schemes given below. In Scheme 1, the compounds of Formula (I) are prepared wherein X and Y = H, n = 1 (butwould also apply if n = 2 or 3 with the corresponding change in the reagent), T = P0 3 H 2 , and Q, A and Z = CH. Scheme 1 (4) (5) a compound of Formula (I) Scheme 2 prepares the compounds of Formula (I) wherein X and Y = H, n = 1 (but would also apply if n = 2 or 3 with the corresponding change in the reagent), T ft -P-OH ; where R 1 = -OJC.-C,. alkyl); and Q, A and Z = CH. Scheme 2 Scheme 3 prepares the compounds of Formula (I) wherein X and Y = H, n = 1 (but would also apply if n = 2 or 3 with the corresponding change in the reagent), T -^>-0H ; R 1 where R 1 = C -C alkyl; and Q, A and Z = CH. Scheme 3 und of Formula (I) Scheme 4 prepares the compounds of Formula (I) wherein X and Y = H, n = 1 (but would also apply if n = 2 or 3 with the corresponding change in the reagent), T where R 1 = -0-(C -C, alkyl) or C -C alkyl; A = C-Br, and Q and Z = CH. Scheme 4 Scheme 4 Cont'd Scheme 5 preparesthe compounds of Formula (I) wherein X and Y = H, n 1 (butwould also apply if n = 2 or 3 with the corresponding change in the reagent), T where R 1 = -OJC.-C 3 alkyl) or C.-C 5 alkyl; A = R 4 = H, NO, NH 2 or SCN; and Q and Z = CH. Scheme 5 (22) (23) Scheme 5 Cont'd Scheme 5 Cont'd Schemeδpreparesthecompoundsof Formula (I) wherein X and Y = H, n = 1 (but would also apply if n = 2 or 3 with the corresponding change in the reagent), T ft -P-OH; where R 1 = -0-(C.-C 5 alkyl) or C.-C 5 alkyl; A = C-OR 8 , where R 8 = C.-C 5 alkylamino; and QandZ = CH. Scheme 6 Cont'd CH3CN Scheme 6 Cont'd a compound of Formula (I) Scheme 6 Cont'd Scheme 7 prepares the compounds of Formula (I) wherein X and Y = H, n = 1 (but would also apply if n = 2 or 3 with the corresponding change in the reagent), T where R 1 = -OH, -OJC.-Q. alkyl) or C.-C 5 alkyl; Z = C-C(0)-R 6 , where R6 = OH; and Q and A = CH. Scheme 7 Cont'd a compound of Formula (I) a compound of Formula (I) a compound of Formula (I) Scheme 8 prepares the compounds of Formula (I) wherein X and Y = H, n = 1 (but would also apply if n = 2 or 3 with the corresponding change in the reagent), T = where R 1 = -OH, -0-(C.-C 5 alkyl) or C.-C 5 alkyl; Z = C-CH 2 -OR 3 where R 3 = benzyl; and Q and A = CH. Scheme 8 a compound of Formula (I) Scheme 8 Cont'd Scheme 8 Cont'd a compound of Formula (I) a compound of Formula (I) Scheme 8 Cont'd 0 II HP(OEt) 2 a compound of Formula (I) Scheme 9 prepares the compounds of Formula (I) wherein X and Y = H, n = 1 (but would also apply if n = 2 or 3 with the corresponding change in the reagent), T where R 1 = -OH, -0-(C.-C 5 alkyl) or C.-C 5 alkyl; A = N or N-R 5 ; R 5 = C.-C 16 alkyl halide; and Q and Z = CH. a compound of Formula (I) a compound of Formula (I) a compound of Formula (I) Scheme 9 Cont'd Scheme 10 prepares the compounds of Formula (I) wherein X and Y = H, n = 1 (but would also apply if n = 2 or 3 with the corresponding change in the reagent), T ft -P-OH ; where R 1 = -OH, -0-(C.-C 3 alkyl) or C.-C 5 alkyl; Q = N-R 5 ; R 5 = C C ι6 alkyl halide; and A and Z = CH. Scheme 10 Scheme 10 Cont'd Scheme 11 preparesthecompoundsof Formula (I) wherein X and Y = H, n Scheme 11 a compound of Formula (I) Scheme 11 Cont'd Alternate synthetic procedures allow selective introduction of the phosphonate at the N-6 position. This phosphonate addition is accomplished by the reaction of (4) with formaldheyde sodium bisulfite addition to give quantitative conversion to the 4,9- substituted sulfonate derivative, which is then converted to the corresponding nitrile. Sebsequent phosphonomethylation and hydrolysis yields the desired product. Scheme 12 prepares the compounds of Formula (I) wherein X and Y = H, n = 1 (but would also apply if n = 2 or 3 with the corresponding change in the reagent), Rat the 3 position has T = ft -P-OH ; 1, 1 where R 1 = -OH or -0-(C.-C 5 alkyl); and the other two R terms have T = COOH; and A. Q and Z = CH. Scheme 12 compound of Formula (I) Scheme 13 preparesthecompoundsof Formula (I) wherein X and Y = H, n = 1 (but would also apply if n = 2 or 3 with the corresponding change in the reagent), R atthe 3 and 6 positions have T = where R' = OH or -0-(C.-C 5 alkyl); and the other Rterm atthe 9 position has T = COOH; and A,QandZ = CH. Scheme 13 Scheme 14 prepares the compounds of Formula (I) wherein X and Y = H, n = 1 (butwould also apply if n = 2 or 3 with the corresponding change in the reagent), R terms atthe 3 and 9 positions have T = where R 1 = -OH or -0-(C.-C 5 alkyl); and the other R term at the 6 position has T = COOH; and A, Q and Z = CH. Scheme 14 (108) a compound of Formula (I) Scheme 15 preparesthecompoundsof Formula (I) wherein n = 1 (but would alsoapply if n = 2 or 3 with the corresponding change in the reagent), R terms at the 3 and 9 positions have T = where R 1 = -OH or -OJC.-C 5 alkyl); and X and Y = H; the R term at the 6 position has T = where R 4 = N0 2 or NH 2 ; and one of Xor Y = H and the other = COOH; and A,QandZ = CH. σv o Scheme 15 Cont'd (HI) (112) compound of Formula (I) Scheme 15 Cont'd (HO) Scheme 16 prepares the compounds of Formula (I) wherein n = 1 (but would also apply if n = 2 or 3 with the corresponding change in the reagent), R terms at the 3 and 6 positions have T = ft -P-OH ; where R 1 = -OH or -OJC.-C 5 alkyl); and X and Y = H; the R term at the 9 position has T = where R 4 = N0 2 or NH 2 ; and one of X orY = H and the other = COOH, A, Q and Z = CH. Scheme 16 (109) compound Scheme 16 Cont'd (118) (117) a compound of Formula (I) compound of Formula (I) Scheme 17 prepares the compounds of Formula (I) wherein n = 1 (but would also apply if n = 2 or 3 with the corresponding change in the reagent), the R term atthe 6 position hasT = where R 1 = -OH; and X and Y = H; the R term at the 3 and 9 positions have T = COOH; and A. Q and Z = CH. In the above Schemes, the general process discription illustrates specific steps that may be used to accomplish a desired reaction step. The general description of these process steps follows. The synthetic Scheme 1 begins with a halogenation of commercially available bis- pyridyl 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 similarily 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. 54, 2990-2992 (1989)]. Detosylation of the intermediate macrocycle [(3) to yield (4)] was accomplished under acidic conditions in good yield. Reductive detosylation procedures are also well known in the literature and can be adapted to the present reaction sequence. Phosphonomethylation to obtain the tris-aminophosphonic acid derative (5, PCTMP) was conducted under typical Mannich base conditions using phosphorous acid and formaldehyde. In addition to phosphonic acid derivatives, phosphonate esters [e.g. of formula (6)] can also be prepared under organic conditions in alcohols or aprotic solvents (e.g. acetonitrile, benzene, toluene, tetrahydrofuran) and using the desired dialkyl phosphite as the nucleophilic species (see Scheme 2). Depending upon the reactivity of the ami ne, these reactions may be conducted at a temperature between about -10 to about 100°C. In addition, trialkylphosphites can be employed under similar Mannich conditions to give the phosphonate ester via oxidation of phosphorous (III) to phosphorous (V) with simultaneous expulsion of one mole of alcohol (Arbuzov reaction). These reactions can be conducted with or without the presence of a solvent. When alcohols are employed as the solvent for either dialkyl or trial kyl phosphite reactions, it is beneficial to use the alcohol from which the corresponding phosphonate ester is derived in order to avoid alternative products arising from transesterification. Esters of this type are also prepared via N-alkylation of α-halo- dialkylphosphonates 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. The resulting perester intermediate is then readily hydrolyzed under basic conditions (aqueous hydroxide, pH = 8-14, 30-110°C) to give the corresponding half-acid derivative. In Scheme 3, macrocyclic methylphosphinic acids (10 and 1 1) are prepared under conditions similar to those described in Scheme 2. Using diethoxymethylphosphine as the nucleophilic species and paraformaldehyde, condensation can be conducted in solvents such as tetrahydrofuran, dimethylformamide, dioxane, acetonitrile or alcholic media. The resulting phosphiπate 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 methyl phosphonic acid. Alternatively, the method devised by A. D. Sherry et al. {Inorg. Chem., submitted 1991) using ethylphosphonic 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 tertaazamacrocycle. Thus, chelidamic acid (Sigma Chemical Company; 12) can be converted to 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. [Ada Chemica Scandinavica B 42, 373- 377(1988)]. Subsequent macrocyclization using this intermediate (15) can be accomplished by the standard DMF reaction at 100°C with the sodiotritosylated triamine, or at room temperature with the tritosylated free base and potassium carbonate, sodium carbonate, or cesium carbonate as base to give products similar to those previously described. Subsequent reactions leading to phosphonate half-acids and phosphinate functionality are identical to those transformations and conditions described in the preceeding Schemes. In Scheme 4, 4-halopyridyl substituted macrocycies (16) are described which can undergo substitution at the 4-position of the pyridyl moiety as described in Scheme 5. Thus, organometallic Pd(ll) 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°Cfor optimum yields. The identical product can also be obtained using Cu(l) phenylacetyiide in anhydrous pyridine at a temperature between about 80 to about 1 10°C. In addition, standard anionic alkylation procedures can be employed to affect substitution on the pyridine nucleus with, for example, sodioalkoxides in DMF or dioxane at from about 80 to about 100°C using bases such as potassium carbonate or sodium hydroxide. Macrocyclic tetraazamacrocycles (24, 25, 26, 27, 28) dervatized in this manner are compatible with transformations described in previous Schemes resulting in analogous phosphonate chelants. A variation of 4-pyridyl substitution is described in Scheme 6 whereby the 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 butyllithium at temperatures between from about -30 to about 80°C. The generality of this approach has been described by Chaubet et al. for acyclic analogs [Tetrahedron Letters 31 (40), 5729-5732 (1990)]. The macrocyclic nitrile prepared in this manner can be reduced to the primary amine (36) by standard procedures followed by protection of the primary amine with 2-(t-butoxycarbonyloxyimino)-2-phenylacetonitrile (BOC-ON; 37) . Subsequent functionalization of the macrocyclic secondary amines (38, 39, 40, 41, 42, 43) can then be accomplished by the procedures discussed with the additional requirement that the BOC protecting group be removed using trifluoroacetic acid as described in Scheme 6. Functionalization can also be carried out on the 3-position of the pyridine ring within the macrocyclic structure as illusatrated in Scheme 7. Newkome et al. [Tetrahedron 39(12), 2001-2008 (1983)1 has previously described the synthesis of ethyl 2,6- halomethylnicotinate (45) which serves as the inital starting material in this synthetic route. Thus, the tris-tosylated macrocycle intermediate (46) can be detosylated under acidic o 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 detosylation 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 chelants of Formula (I) (49, 50, 51 , 52, 53). 5 In contrast, 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 detosylation step. After appropriate functionalization of the secondary amines has been accomplished as described in previous Schemes, the benzyl group is removed under mild 0 catalytic hydrogenation conditions (58). Macrocyclic derivatives can also be prepared as in Schemes 12-14 where both carboxylate and phosphonate chelating fuctionalities are present in the same molecule. Thus, varying degrees of carboxylate fuctionality can be introduced under typical aqueous alkylation procedures using bromoaceticacid. Following this step, the remaining amines can be phos- 5 phonomethylated by procedures discussed in previous Schemes using formaldehyde and phosphorous acid, dialkyl phosphonates or trialkyl phosphites. Schemes 15 and 16 delineate a synthetic approach which introduces an aromatic nitrobenzyl substitutent at one of the macrocyclic nitrogen positions. Typically, the macrocyclic amine is mono-N-functionalized in an organic solvent such as acetonitrile or DMF at room 0 temperature using a non-nucleophilic base such as potassium carbonate. Additional functionalization of the remaining nitrogen positions is then performed by methodsand conditions described in previous Schemes. After the introduction of the desired chelating moieties, the nitro group is reduced using platinum oxide and hydrogen in water. In this form, the chelating agent is compatible with conjugation techniques which will enable attachment 5 to larger synthetic or natural molecules. Scheme 17 illustrates the synthesis of the macrocyclic compounds (4) where the amines at positions 3 and 9 are reacted with at least two moles of the sodium salt of hydroxymethanesulfonic acid in water at a pH of about 9 to provide the corresponding macrocyclic compound where positions 3 and 9 are the sodium salt of methanesulfonic acid (119). The sulfonic acid group is then displaced using sodium cyanide to form the corresponding cyanomethane derivative (120). The cyano group is hydrolyzed to the carboxylic acid either: simultaneously with the addition of phosphorous acid and formaldehyde; or by sequential reaction with a derivative of phosphorous acid and formaldehyde to form the phosphonic acid at the 6 position (121), followed by acid hydrolysis, at an elevated temperature, of the cyanato groups and any derivative moiety of the phosphorous acid present. The resulting compound is a macrocycle with two carboxylic acid groups at positions 3 and 9 and a phosphonic acid group at position 6. The phosphonomethylation can also be preformed bythe methods discussed above. The metal ions used to form the complexes of this invention are Gd +3 , Win *2 , Fe ÷ 3 and available commercially, e.g. from Aldrich Chemical Company. The anion present is halide, preferrably chloride, or salt free (metal oxide). A "paramagnetic nuclide" of this invention means a metal ion which displays spin angular momentum and/or orbital angular momentum. The two types of momentum combine to give the observed paramagnetic moment in a manner that depends largely on the atoms bearing the unpaired electron and, to a lesser extent, upon the environment of such atoms. The paramagnetic nuclides found to be useful in the practice of the invention are gadolinium (Gd + 3 ), iron (Fe * 3 ) and manganese (Mn +2 ), with Gd +3 being preferred. 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 amino acids in Synthetic Production and Utilization of Amino AcidsJedited 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 paramagnetic nuclide composition, e.g. stable to the disassociation of the paramagnetic nuclide 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. The 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, Kohlerand Milstein [Nature. 256, 495-497 (1975); and fur. J. Immunol., 6, 51 1-519 (1976)]. Such antibodies normally have a highly specific reactivity. In the antibody targeted conjugates, antibodies directed against any desired antigen or hapten may be used. Preferably 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 fragraments are 1 1 16-NS-19-9, 1 1 16-NS-3d, 703D4, 704A1 , CC49, CC83 and B72.3. All of these antibodies have been deposited in ATCC. A more complete list of antigens can be found in U.S. Patent 4,193,983. The conjugates of the present invention are particularly preferred for the diagnosis of various cancers. This invention is used with a physiologically acceptable carrier, excipient or vehicle therefore. The methods for preparing such formulations are well known. The formulations 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. 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. Other uses of some of the chelants of the present invention may include the removal of undesirable metals (i.e. iron) from the body, attachment to polymeric supports for various purposes, e.g. as diagnostic agents, and removal of metal ions by selective extraction. The ligands of Formula (I) having in at least two R terms T equal to (0)R'OH may be used for metal ion control as scale inhibitors. Some of these ligands can be used in less than stoichiometric amounts. Similar uses are known for compounds described in U.S. Patents 2,609,390; 3,331 ,773; 3,336,221 ; and 3,434,969. The invention will be further clarified by a consideration of the following examples, which are intended to be purely exemplary of the present invention. Some terms used in the following examples are defined as follows: LC = liquid chromatrography, purifications were carried out at low pressure using Dionex 2010i system fitted with a hand-packed Q-Sepharose'" anion exchange column (23 x 2 cm). DMF = dimethylforamide. AcOH = acetic acid. ICP = inductively coupled plasma. g = gram(s). mg = milligrams. kg = kilogram(s). mL = milliliter(s). μl_ = microliter(s). pH Stability General Procedure A stock ,59 GdCI 3 (or 153 SmCI 3 ) solution was prepared by adding 2 μL of 3x10 "4 M ,59 GdCI 3 in 0.1 N HCl to 2 mL of a 3x1 O^M GdCI 3 carrier solution. Appropriate ligand solutions were then prepared in deionized water. The 1 : 1 ligand/metal complexes were then prepared by combining the ligands (dissolved in 100-500 μL of deionized water) with 2 mL of the stock ,59 GdCI 3 solutionJollowed by through mixing to give an acidic solution (pH = 2). The pH of the solution was then raised to 7.0 using 0.1 N NaOH. The percent metal as a complex was then determined by passing a sample of the complex solution through a Sephadex'" G-50 column, eluting with 4: 1 saline (85% NaCI/NH 4 OH) and collecting 2 x 3 mLfractions. The amount of o 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 1 M NaOH or 1M HCl and determining the percent of the metal existing as a complex using the ion exchange method described above. The Sm results are known by expermintal comparison to be identical for complexation and 5 biodistribution of the ligands of this invention. STARTING MATERIALS Example A Preparation of 2,6-bis(chloromethyl)pyridine. ' To lOO mL of thionyl chloride that was cooled (ice bath) was added 24 g (0J7 mol) 0 of 2,6-bis(hydroxymethyl)pyridine. After 30 min, the reaction mixture was warmed to room temperature, then refluxed for 1.5 hrs. After cooling the reaction mixture to room temperature, the solid which formed was filtered, washed with benzene and dried in vacua. The solid was then neutralized with saturated NaHC0 3 , filtered and dried to yield 23.1 g (71.5%) of the titled product as an off-white crystalline solid, mp 74.5-75.5°C, and further 5 characterized by: 'H MR fCDC δ 4.88 (s, 4H), 7.25-7.95 (m, 3H). Example B Preparation of 3,6,9-tris(p-tolylsulfonyl)-3,6,9J 5-tetraazabicyclo[9.3J ]pentadeca-1{15)J 1 ,13- triene. A DM F solution (92 mL) of 6.9 g (1 1.4 mmol) of 1 ,4,7-tris(p- tolylsulfonyl)diethylenetriamine disodium salt was stirred and heated to 100°C under nitrogen. To the solution was added dropwise over 45 min 2 g (1 1.4 mmol) of 2,6- bis(chloromethyl)pyridine (prepared by the procedure of Example A) in 37 mL of DMF. When the addition was completed the reaction mixture was stirred at40°C for 12 hrs. To the reaction mixture was then added 50-75 mL of water, resulting in immediate dissolution of NaCI, followed by precipitation of the title product. The resulting slurry was then filtered and the solid washed with water and dried in vacuo. The title product was obtained as a light-tan powder, 6.5 g (86%), mp 168-170°C dec. and further characterized by: ■ H NMR (CDCI 3 ) δ 2.40 (s, 3H), 2.44 (s, 6H), 2.75 (m, 4H), 3.30 (m, 4H), 4.28 (s, 4H), 7.27 (d, 2H), 7.34 (d, 4H), 7.43 (d, 2H), 7.65 (d, 4H), 7.75 (t, 1 H); and ,3 C NMR 5 621.48, 47.29, 50.37, 54.86, 124.19, 127.00, 127.11 , 129.73, 135.04, 135.74, 138.95, 143.42, 143.73, 155.15. Example C Preparati on of 3,6,9, 15-tetraazabicyclo[9.3.1 ] pentadeca- 1 ( 15), 1 1 J 3-triene. Asolution of HBr and AcOH was prepared by mixing 48% HBr and glacial AcOH in 10 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- tolylsυlfonyl)-3,6,9,15-tetraazabicyclo[9.3J]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 concentrated to approximately 1/10 of the original volume. The remaining solution was stirred 15 vigorously and 15-20 mL of diethyl ether was added. A off-white solid formed which was filtered, washed with diethyl ether, and dried in vacuo. The dry tetrahydrobromide salt was then dissolved in 10 mL of water, adjusted to pH 9.5 with NaOH (50% w/w) and continuously extracted with chloroform for 4 hrs. After drying over anhydrous sodium sulfate, the chloroform was evaporated to give a light-tan oil which gradually crystallized upon standing at 20 room temperature to yield 1.2 g (71 %) of the title product, mp 86-88°C and further characterized by: Η NMR (CDCI 3 ) δ 2.21 (m, 4H), 2.59 (m, 4H), 3.06 (s, 3H), 3.85 (s, 4H), 6.89 (d, 2H), 7.44 (t, 1H); and ,3 C MR 25 648.73, 49.01, 53.63, 1 19.67, 136.29, 159.54. Example D Preparation of 3,6,9, 15-tetraazabicyclo[9.3.1 ]pentadeca-1 (15), 1 1 ,13-triene-3,9- dimethyienesulfonic acid. A slurry of 500 mg (2.4 mmol) of 3,6,9,15-tetraazabicyclo[9.3.1 ]pentadeca- 30 1 (15), 1 1 , 13-triene (prepared bythe procedure of Example C) was stirred in 6 mL of water and the pH adjusted to 3 using 6M HCl. To the mixture was added 682 mg (5.1 mmol) of hydroxymathanesulfonic acid sodium salt and the pH adjusted to 9 with 50% aqueous sodium hydroxide. After stirring for three hrs at room temperature, ,3 C NMR indicated complete conversion to the title bis-methylenesulfonic acid product. 35 Example E Preparation of 3,6,9J 5-tetraazabicyclo[9.3.1]pentadeca-1 (15)J 1J3-triene-3,9- dimethylenenitrile. Tothe reaction mixture containing 3,6,9,15-tetraazabicyclo[9.3.1 ]pentadeca- 1(15)J 1 J3-triene-3,9-dimethylenesulfonic acid from Example D was added 47 mg (9.6 mmol) of sodium cyanide. The reaction mixture was stirred at room temperature for 24 hrs. 13 C MR indicated that transformation to the bis-nitrile was complete. The reaction mixture was then filtered, extracted three x 25 mL with chloroform, dried over anhydrous magnesium suifate, and concentrated to give a viscous oil. The oil was then disolved in chloroform, triturated with o cyclohexane, and concentrated to give, as white powder, 530 mg (78%) of the title dimethylenenitrile product. Example F Preparation of 3,9-bis(sodium methylenesulfonate)-3,6,9, 15-tetraazabicyclo[9.3.1 ]pentadeca- 1(15)J 1 J3-triene (PC2S). 5 An aqueous solution (10.0 mL) of 3,6,9, 15-tetraazabicyclo[9.3.1 ]pentadeca- 1(15)J 1 ,13-triene (prepared by the procedure of Example C), 1.03 g (5.0 mmol) was added with 0.5 mL of concentrated HCl and stirred for 10 min to ensure complete dissolution. The resulting solution had a pH of 8.6. Tothe solution was then added 1.37 g (10.2 mmol) of HOCH 2 SO Na with 5 mL of deionized water. The solution was heated at 60°C for 10 min and the pH dropped 0 to 5.6. After cooling, the pH was adjusted to 9.0 with 1M aqueous sodium hydroxide, followed by lyophilization to give the desired product as a white solid in a quantative yield and characterized by: 'H MR fD. ) δ 2.87 (t, 4H), 3J8 (t, 4H), 3.85 (s, 4H), 4.1 1 (s, 4H), 7.03 (d, 2H), 7.55 (t, 1 H); and 5 13 C NMR (D 2 0) δ 48.52, 54.04, 58.92, 79.09, 123.90, 141.37, 161.89. Example G Preparation of 3,9-bis(methylenenitrile)-3,6,9J 5-tetraazabicyclo[9.3.1]pentadeca-1 (15), 1 1 ,13- triene. 0 To an aqueous solution, 10.0 mL, of 3,9-bis(sodium methylenesulfonate)-3,6,9J 5- tetraazabicyclo[9.3.1]pentadeca-1(15),11,13-triene (prepared bythe procedure of Example F), 2.26 g (5 mmol), was added 0.6 g (12.24 mmol) of sodium cyanide. The mixture was stirred for 3 hrs at room temperature. The pH of the reaction mixture was about 10. The pH was adjusted to above 13 with concentrated aqueous sodium hydroxide. The product precipitated and was 5 extracted with chloroform (3 x 20 mL), dried over anhydrous magnesium suifate, and filtered. Upon removal of sol vent and concentration in vacuo, the desired product was isolated as a waxy, white powder, 1.0 g (71 %) and characterized by: ' H NMR (CDCI 3 ) δ 2.03 (br s, 4H), 2.64 (m, 4H), 3.82 (s, 4H), 3.90 (s, 4H), 7.14 (d, 2H), 7.62 (t, 1 H); and 13 C NMR (CDCI 3 ) δ 46.08, 46.64, 52.89, 60.78, 1 15.31 , 122.02, 137.57, 157.33. 5 Example H Preparation of 3,9-bis(methylenenitrile)-6-(methylenedimethylphosphonate)-3, 6,9,15- tetraazabicyclo[9.3J ]pentadeca-1(15),1 1 J3-triene-3,9-dimethylenenitrile. 3,9-bis(methylenenitrile)-3,6,9J 5-tetraazabicyclot9J.1 ]pentadeca-1(15)J 1 J 3- triene (prepared by the procedure of Example G), 285 mg (1.0 mmol) was combined with 60 mg 0 (2.0 mmol, excess) of paraformaldehyde and 0.354 mL (372 mg, 3.0 mmol, excess) of trimethylphosphite. The mixture was gently stirred for 10 min to obtain a slurry, then heated to 90°C for 1 hr. After the excess reagents and byproducts were removed in vacuo (1 hr at 125°C/0.01 mmHg), he resulting dark brown residue was dissolved in 20 mL of chloroform and washed with deionized water (5 x 15 mL). The organic layer was dried over anhydrous 15 magnesium suifate, filtered, and the excess solvents evaporated in vacuo to give the desired product as a yellow waxy solid, 168 mg (41 %) and characterized by: Η NMI-UCDCI j ) δ 2.61 (br s, 8H), 2.73 (d, 2H), 3.62 and 3.68 (s, 6H), 3.73 (s, 4H), 3.84 (s, 4H), 7.06 (d, 2H), 7.57 (t, 1 H); and 20 13 C NMR (CDCI 3 ) 544.44, 50.74, 51.03, 51.85, 52.51 , 60.28, 1 15.61 , 122.27, 137.24, 156.61. Example I Preparation of 3,6,9, 15-tetraazabicyclo[9.3.1 ]pentadeca-1 (15), 1 1 , 13-triene-3,6,9- methylenediethyl phosphonate. 25 A mixture of 1 g (4.8 mmol) of 3,6,9,15-tetraazabicyclo[9.3.1 ]pentadeca- 1(15)J 1J3-triene (prepared bythe procedure of Example C), 4.8 g (28.8 mmol) of triethyl phosphite and 864 mg (28.8 mmol) of paraformaldehyde was heated at 90°C with constant stirring for 45 min. The reaction mixture was concentrated in vacuo and the viscous oil chromatographed on a basic alumina column, eluting with chloroform. After concentration of 30 the organic eluent, the desired product was isolated as a colorless oil, 2.0 g (64%) and characterized by: 'H MR fCDCy δ 1.23 (m, 18H), 2.77 (m, 12H), 3.04 (d, 6H), 4.13 (m, 12H), 7.17 (d, 2H), 7.60 (t, 1 H); and 13 C NMR (CDCI 3 ) 35 δ 16.43, 50.03, 50.31 , 50.43, 50.77, 51.23, 51.38, 52.63, 53.30, 60.86, 60.92, 61.63, 61.74, 61.83, 61.93, 62.32, 76.46, 76.97, 77.18, 77.48, 122.50, 137.10, 157.18; and 31 P MR δ 24.92 (s, 2P), 24.97 (sJ P). Example J Preparation of 3,6,9,15-tetraazabicyclo[9.3.1 ]pentadeca-1 ( 15), 1 1 ,13-triene-3,6,9- methylenedi(n-propyl)phosphonate. To 3 mL of a chloroform/dioxane solution (1 : 1) was added 100 mg (0.48 mmol) of 5 3,6,9,15-tetraazabicyclo[9.3.1]pentadeca- 1(15), 11 ,13-triene (prepared bythe procedure of Example C), 318 mg (1.53 mmol) of tripropyl phosphite and 46 mg (1.53 mmol) of paraformaldehyde. The reaction mixture was heated at 90°C with stirring for 1 hr. The resulting homogenous solution was concentrated in vacuo to give a viscous oil which was chromatographed on a neutral alumina column, eluting with chloroform. After concentration 10 of the organic eluent, the desired product was isolated as a colorless oil, 320 mg (90%) and characterized by: 'H NMR fCDC δ 0.88 (m, 18H), 1.61 (m, 12H), 2.72 (m, 12H), 3.03 (d, 6H), 3.97 (m, 12H), 7.13 (d, 2H), 7.55 (t, 1 H); and 15 13 C NMR (CDCI 3 ) δ 9.96, 23.73, 49.84, 50.14, 50.26, 50.57, 51.1 1, 51.23, 52.43, 53.01, 60.78, 60.84, 67.27, 67.40, 122.48, 137.04, 157.16; and 31 P NMR δ 24.98 (3P). 20 Example K Preparation of 3,6,9,15-tetraazabicydo[9.3.1 ]pentadeca-1 (15),1 1 ,13-triene-3,6,9- methylenedi(n-butyl)phosphonate. A mixture of 500 mg (2.4 mmol) of 3,6,9, 15-tetraazabicyclo[9.3.1 ]pentadeca- 1 ( 15), 11 , 13-triene (prepared by the procedure of Example C), 2.0 g (8 mmol) of tributyl 25 phosphite and 240 mg (8 mmol) of paraformaldehyde was heated at 100°C with stirring for 1 hr. The resulting viscous solution was concentrated in vacuo to give an oil which was chromatographed on a basic alumina column, eluting with chloroform. After concentration of the organic eluent, the desired product was isolated as a colorless oil, 1.25 g (65%) and characterized by: 30 Η NMR (CDCl 3 ) δ 0.84 (m, 18H), 1.27 (m, 12H), 1.58 (m, 12H), 2.57 (m, 12H), 3.01 (d, 6H), 3.99 (m, 12H), 7.12 (d, 2H), 7.54 (t, 1 H); and 13 C NMR (CDCI 3 ) δ 13.42, 13.46, 18.50, 18.59, 32.16, 32.43, 49.88, 50.03, 50.16, 50.63, 51.1 1, 51.27, 52.48, 53.16, 35 60.71 , 60.78, 65.38, 65.48, 65.58, 122.46, 136.96, 157.14; and 3, P NMR δ 24.88 (2P), 24.93 (1 P). Example L Preparation of 3,6,9,15-tetraazabicyclo[9.3.1]pentadeca-1 (15), 1 1 ,13-triene-3[(4- nitrophenyl)methyl acetate]. To a solution of 2.5 mL of chloroform which was rapidly stirred and 200 mg (0.97 mmol) of 3,6,9, 15-tetraazabicyclo[9.3.1 ]pentadeca- 1 ( 15), 1 1 J 3-triene (prepared by the procedure of Example C), was added in one portion 266 mg (0.97 mmol) of bromo(4- nitrophenyl)methyl acetate in 2.5 mL of chloroform. The reaction mixture was stirred for 24 hrs at room temperature. The solution was concentrated in vacuo to give a semi-solid which was chromatographed on a silica gel column, eluting with chloroform/methanol/ammonium hydroxide (16:4: 1). After concentration of the organic eluent, the desired product was isolated as a light yellow solid, 250 mg (64%) and characterized by: 13 C MR (CDCI 3 ) δ 45.67, 45.90, 45.97, 51.65, 52.08, 52.28, 53.78, 69.54, 1 19.03, 1 19.23, 122.85, 130.30, 137.06, 143.27, 147.05, 159.59, 160.41, 171.70. FINAL PRODUCTS Example 1 Preparation of 3,6,9,15-tetraazabicyclo[9.3.1 lpentadeca- 1 (15), 1 1 , 13-triene-3, 6,9- trimethylenephosphonic acid (PCTMP). A mixture of 2.06 g (10 mmol) of 3,6,9,15-tetraazabicyc!o[9.3.1 ]pentadeca- 1(15), 1 1,13-triene (prepared bythe procedure of Example C), 1 1.3 g (138 mmol) of phosphoric acid and 15 g (152 mmol) of concentrated HCl was heated to gentle reflux (103 °C) with constant stirring followed by the dropwise addition (2 ml_/min) of 12.2 g (150 mmol, 15 mL) of aqueous formaldehyde (37%). After complete addition, the reaction mixture was stirred at reflux for 16 hrs, cooled to room temperature and concentrated to a thick, viscous oil. The product was then purified by LC anion exchange chromatography (0-30% formic acid, 3 mL/min, retention time = 32 min). The combined fractions were freeze-dried to give 4.8 g (99%) of the title product as a white solid, mp 275-280°C and further characterized by: , H NMR (D 2 0) δ 2.83 (m, 6H), 3.46 (m, 10H), 7.28 (d, 2H), 7.78 (t, 1 H); and ,3 C NMR δ 53.61, 53.81, 55.27, 57.93, 62.20, 125.48, 143.08, 152.31 ; and 31 P NMR δ 8.12 (2P), 19.81 (1 P). Example 2 Preparation of the complex of 153 Sm-3, 6,9,15-tetraazabicyclo[9.3.1 ]pentadeca-1 (15),1 1 J 3- triene-3,6,9-trimethylenephosphonic acid ( 153 Sm-PCTMP). A solution of the ligand of Example 1 was prepared by dissolving 3.8 mg of ligand/0.517 mL of deionized water (pH = 2). A 1 : 1 ligand/metal complex was then prepared by combining 40 μl of the ligand solution with 2 mL of aqueous SmCI 3 *H.,0 (3x1 O^M in 0.01 N HCl) contai ning tracer 153 SmCI 3 . After thorough mixing, the percent metal as a complex was determined by passing a sample ofthe complex solution through a Sephadex™ column, eluting with 4: 1 saline (0.85% NaCI/NH 4 OH), and collecting 2 x 3 mL fractions. The amount of radioactivity in the combined el utions was then compared with that left on the resin. Under these conditions, complex was removed with the eluent and non-complexed metal is retained on the resin. By this method complexation was determined to be 98%. A sample of the solution that was passed through the resin was used for pH studies. The pH stability was then determined using the General Procedure above. Example 3 Preparation of 3,9-diacetic acid-6-(methylenephosphonic acid)-3,6,9, 15- tetraazabicyclo[9.3.1 ]pentadeca-1 (15)J 1 , 13-triene (PC2A1 P). A concentrated hydrocholric acid solution (37%, 5 mL) of 3,9-bis(methylene- nitri le)-6-(methylenedimethyl phosphonate)-3, 6,9,15-tetraazabicyclo[9.3.1 Jpentadeca- 1(15),1 1J3-triene (prepared in Example H), 168 mg (1.0 mmol) was heated at reflux for 16 hrs. After cooling, the solution was evaporated to dryness, followed by coevaporation with deionized water (2 x 10 mL) to remove the excess hydrochloric acid. The filal product was isolated as a dark brown solid upon lyphilization of the concentrated queous solution and characterized by: 'H NMR ^O) 62.68 (br s, 4H), 3.31 (br s, 4H), 4.08 (s, 4H), 4.55 (s,4H), 7.16 (d, 2H), 7.68 (t, 1 H); and 13 C NMR (D 2 0) δ 52.35, 54.04, 57.02, 59.24, 62.26, 125.52, 143.64, 152.36, 171.54; and 3 P NMR (D 2 0) δ 20.03. Example 4 Preparation of 3,6,9, 15-tetraazabicyclo[9.3.1 ]pentadeca-1 (15), 11 J 3-triene-3,6,9- methyleneethylphosphonate tris(potassium salt) (PMEHE). To an aqueous 0.1 N potassium hydroxide solution (2 mL) was added 250 mg (0.38 mmol) of 3,6,9, 15-tetraazabicyclo[9.3.1 ]pentadeca-1 (15), 1 1 J 3-triene-3,6,9-methylene- di ethyl phosphonate (prepared by the procedure of Example I). The solution was heated at 90°C for 5 hrs. The reaction mixture was cooled to room temperature, filtered, and freeze- dried to yield the desired product as an off-white solid, 252 mg (97%) and characterized by: ,3 C MR (D 2 0) δ 18.98, 19.82, 51.78, 52.06, 53.08, 54.46, 54.68, 57.01 , 58.22, 60.24, 63.19, 63.25, 63.36, 63.49, 63.59, 63.95, 64.18, 64.25, 66.80, 126.62, 141.63, 159.40; and 3, P NMR δ 20.58 (s, 2P), 20.78 (s, 1 P). Example 5 Preparation of 3,6,9, 15-tetraazabicyclo[9.3.1 ]pentadeca-1 ( 15), 1 1 , 13-triene-3,6,9-methylene(n- propyl)phosphonate tris( potassium salt) (PMPHE). To an aqueous solution of potassium hydroxide (0.5 mL of 1 N/dioxane (0.5 mL) was added 81 mg (0J08 mmol) of 3,6,9J5-tetraazabicyclo[9.3.1 ]pentadeca-1 (15),1 1J3-triene- 3,6,9-methylenedi(n-propyl)phosphate (prepared bythe procedure of Example J). The solution was heated at reflux for 24 hrs. The reaction mixture was cooled to room temperature and extracted with diethyl ether. The ether extract was then concentrated in vacuo to yield the desired product as an off-white solid, 48.6 mg (60%) and characterized by: 3, P NMR δ 20.49 (s, 3P). Example 6 Preparation of 3,6,9, 15-tetraazabicyclo[9.3.1 ]pentadeca-1 ( 15), 1 1 J 3-triene-3,6,9-methylene(n- butyl) phosphonate tris(potassium salt) (PMBHE). To an aqueous solution of 35 mL of 1 N potassium hydroxide was added 3.21 g (3.88 mmol) of 3,6,9,15-tetraazabicyclo[9.3.1 ]pentadeca-1(15),1 1 ,13-triene-3,6,9- methylenedi(n-butyl)phosphate (prepared by the procedure of Example K). The solution was heated at reflux for 5 days. The reaction mixture was cooled to room temperature, filtered and the filtrate freeze-dried to give a cream colored solid. The solid was then suspensed in 150 mL of methanol and stirred for 12 hrs at room temperature. The slurrywas then filtered and the filtrate concentrated to give a semi-solid. The solid was taken up in 150 mL of chloroform and dried over anhydrous sodium suifate and filtered. After concentration in vacuo the product was isolated as an off-white solid, 1.86 g (62%) and characterized by: Η NMR (D 2 0) δ 0.68 (m, 9H), 1.14 (m, 6H), 1.37 (m, 6H), 2.76 (d, 6H), 3.41 (m, 12H), 3.73 (m, 6H), 7.24 (d, 2H), 7.76 (t, 1 H); and 13 C MR (D 2 0) δ 15.76, 15.80, 21.12, 21.20, 34.96, 35.06, 35.14, 52.08, 52.53, 53.38, 53.48, 54.49, 54.75, 57.70, 57.76, 61.86, 67.65, 67.75, 67.98, 68.08, 125.15, 142.93, 152.25; and 3, P NMR δ 9.73 (s, 2P), 21.00 (s, 1 P). Example 7 Preparation of 3,6,9, 15-tetraazabicyclo[9.3.1 ]pentadeca-1 (15),1 1 ,13-triene-3[(4- nitrophenyl)methyl acetate]-6,9-methylenediethylphosphonate. A solution of 250 mg (0.62 mmol) of 3,6,9,15-tetraazabicyclo[9.3.1 ]pentadeca- 1(15), 1 1 J 3-triene-3[(4-nitrophenyl)methyl acetate] (prepared by the procedure of Example L), 624 mg (3.7 mmol) of triethyl phosphite, and 1 1 1 mg (3.7 mmol) of paraformaldehyde was stirred at 100°C for 1 hr. The reesulting homogeneous solution was concentrated in vacuo to give a viscous oil. The oil was dissolved in 10 mLof chloroform and washed with water (3 x 5 mL). The organic layer was dried over anhydrous magnesium suifate, filtered and the filtrate concentrated in vacuo to give the product as aviscous oil, 326 mg (96%) and characterized by: 31 P NMR (CDCI 3 ) 5 δ 24.67 (s, 2P), 24.88 (s, 1 P). BIODISTRIBUTION General Procedure Sprague Dawley rats were allowed to acclimate for five days then injected with 0 100 μL of the complex solution via a tail vein. The rats weighed between 150 and 200 g at the time of injection. After 30 min. the rats were killed by cervical dislocation and dissected. The amount of radioactivity in each tissue was determined by counting in a Nal scintillation counter coupled to a multichannel analyzer. The counts were compared to the counts in 100 μL standards in order to determine the percentage of the dose in each tissue or organ. 15 The percent dose in blood was estimated assuming blood to be 7% ofthe 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. in addition to organ biodistribution, chelates of the compounds of Formula (I) 20 were evaluated for efficiency of bone localization since phosphonates are known fortheir ability to bind to hydroxyapatite. EXAMPLE I The percent of the injected dose of complex of of Example 2 ( 153 Sm-PCTMP) in several tissues are given in Table I. The numbers represent the average of a minimum of 3 rats 25 per data point at 2 hours post injection. TABLE I % INJECTED DOSE IN SEVERAL TISSUES FOR l53Sm-PCTMP 30 35 EXAMPLE II The percent of the injected dose of com lex of of Example 5 ( 153 Sm-PMPHE) in several tissues are given in Table II. The numbers represent the average of a minimum of 3 rats per data point at 2 hours post injection. TABLE I I % INJECTED DOSE 153Sm-PM PHE (2 hours) EXAMPLE III The percent of the injected dose of complex of of Example 6 ( 153 Sm-PMBHE) in several tissues are given in Table III. The numbers representthe average of a minimum of 3 rats per data point at 2 hours post injection. TABLE I I I % INJECTED DOSE i 53Sm-PMBHE (2 hours) EXAMPLE IV The percent ofthe injected dose of complex of of Example 3 ( 153 Sm-PC2A1) in several tissues are given in Table IV. The numbers representthe average of a minimum of 3 rats per data point at 2 hours post injection. TABLE IV % INJECTED DOSE l53Sm-PC2A1 P (2 hours) IMAGING EXPERIMENTS General Procedure Injectable solutions were first prepared (0.5M) by dissolving the appropriate amount of each complex in 2 mL of deionized water. The pH of the solutions were then adjusted to 7.4 using 1M HCl or NaOH as needed. The total Gd content of each solution was then determined by ICP analysis. An anesthetized Sprague Dawley rat was injected intramuscularly with one of the metal solutions described above at a dose of 0.05-0.1 mmol Gd/kg body weight. Images were then taken at various time intervals and compared with a non-injected control at time 0. Example II The Gd-PCTMP complex (prepared in Example 2) showed kidney enhancement and bone localization in the shoulder, spine and sternum. Other embodiments ofthe invention will be apparent to those skilled in the art from a consideration of this specification or practice of the invention disclosed herein. It is intended that the specification and examples be considered as exemplary only, with the true scope and spirit of the invention being indicated by the following claims.

Claims: 1. Bicyclopoiyazamacrocyclophosphonic acid compounds of the formula wherein: ϊ R = - ( C ) n -T ; I Y where: X and Y are independently H, OH, C.-C 3 alkyl or COOH; n is an integer of 1, 2 or 3; with the proviso that: when n is 2, then the sum of X and Y must equal two or more H; and when n is 3, then the sum of X and Y must equal three or more H; T is H, C r C lg alkyl, COOH, OH, S0 3 H, where: R 1 is -OH, C.-C 5 alkyl or -0-(C.-C 5 alkyl); R 4 is H, N0 2 , NH 2 , isothiocyanato, semicarbazido, thiosemicarbazido, maleimido, bromoacetamido or carboxyl; 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; with the proviso that at least one T must be PfOJR'OH, and with the proviso that when one T is -^2 R 4 then one X or Y of that R term may be COOH and all other X and Y terms of that R term must be H; A is CH, N, C-Br, C-CI, C-OR 3 , C-OR 8 , N + -R 5 χ-, R 3 is H, C.-C 5 alkyl, benzyl, or benzyl substituted with at least one R"; R 4 is defined as above; R 5 is C.-C. 6 alkyl, benzyl, or benzyl substituted with at least one R 4 ; R 8 is C.-C. 6 alkylamino; XJs CΪ, Br, r or H 3 CC0 2 ' ; Q and Z independently are CH, N, N + -R 5 X " , C-CH 2 -OR 3 or C-C(0)-R 6 ; R 5 is defined as above; R 6 is -0-(C C 3 alkyl), OH or NHR 7 ; R 7 is C.-C 5 alkyl or a biologically active material; X is defined as above; or pharmaceutically-acceptable salts thereof; with the proviso that: a) when Q, A or Z is N or N + -R 5 X", then the other two groups must be CH; b) when A is C-Br, C-CI, C-OR 3 or C-OR 8 , then both Q and Z must be CH; c) the sum of the R 4 , R 7 and R 8 terms, when present, may not exceed one; and d) only one of Q or Z can be C-C(0)-R 6 and when one of Q or Z is C-C(0)-R 6 , then A must be CH. 2. A compound of Claim 1 wherein at least two R terms have T equal to P(0)R'OH where R 1 is OH and the third T equal H, COOH or C.-C 18 alkyl; A, Q and Z are CH; n is 1 ; and X and Y independently are H or C l -C 3 alkyl. 3. A compound of Claim 1 wherein three R terms have T equal to P(0)R 1 OH where R1 is OH; and X and Y are H, and named as 3,6,9,15-tetraazabicyclo[9.3.1 ]pentadeca- 1 (15),1 1,13-triene-3,6,9-trimethylenephosphonic acid or pharmaceutically-acceptable salts thereof. 4. A compound of Claim 2 wherein in two R terms T is P(0)R'OH, where R 1 is OH, in the third Rterm T is COOH, and n is 1. 5. A compound of Claim 2 wherein in two R terms T is P(0)R 1 OH, where R 1 is OH, in the third R term T is P(0)R'OH, where R' is C.-C 5 alkyl, and n is 1. 6. A compound of Claim 2 wherein in two Rterms T is P(0)R'OH, where R ' is OH, in the third R term T is PtOJR'OH, where R 1 is -0-(C C 5 alkyl), and n is 1. 7. A compound of Claim 1 wherein in the Rterm is at least one T equal P(0)R 1 OH, where R 1 is defined as in Claim 1 , and in the other two R terms, T is COOH or P(0)R 1 OH, and n, R , X, Y, A, Q and Z are defined as in Claim 1. 8. A compound of Claim 7 wherein in one Rterm T is P(0)R'OH, where R 1 is OH, and in the other two R terms T is P(0)R'OH, where R 1 is -0-(C.-C 5 alkyl), and n is 1. 9. A compound of Claim 7 wherein in one R term T is P(0)R'OH, where R 1 is OH, and in the other two R terms T is P(0)R 1 OH, where R 1 is C.-C 5 alkyl, and n is 1. 10. A compound of Claim 7 wherein in one Rterm T is P(0)R'OH, where R 1 is OH, and in the other two R terms T is COOH, and n is 1. 11. Acompoundof Claim 7 wherein inoneRterm TisP(0)R 1 OH where R 1 is OH; intheothertwoRtermsTis COOH; nis 1; and X and Y are H; and named as3,9-diacetic acid-6-(methylenephosphonic acid)-3,6,9, 15-tetraazabicyclo[9.3.1 ]pentadeca-1 (15), 11,13- o triene or pharmaceutically-acceptable salts thereof. 12. Acompoundof Claim 1 wherein inthe Rterm three T equal P(0)R'OH, where R 1 is C.-C 3 alkyl or -0-(C.-C 5 alkyl), and n, R 1 , X, Y, A, Q and Z are defined as in Claim 1. 13. A compound of Claim 12 wherein in the three R terms T is P(0)R 1 OH, where RJs-0-(C C 5 alkyl),andnis1. 5 14. Acompound of Claim 13wherein inthe three R terms T is P(0)R'OH, where R 1 is -0-C 2 H 5 ; and named as 3,6,9, 15-tetraazabicyclo[9.3.1 Jpentadeca- 1 ( 15), 11 ,.3-triene-3,6,9- methyleneethylphosphonate. 15. Acompound of Claim 13 wherein in the three R terms T is P(0)R'OH, where R 1 is -0-C 3 H 7 ; and named as 3,6,9, 15-tetraazabicyclo[9.3.1 ]pentadeca- 1 (15), 11 J 3-triene-3,6,9- 0 methylene(n-propyl)phosphonate. 16. A compound of Claim 13 wherein in the three R terms T is P JR'OH, where R 1 is-0-C 4 H g ; and named as 3,6,9,15-tetraazabicyclo[9.3.1]pentadeca-1(15)J1J3-triene-3,6,9- methylene(n-butyl)phosphonate. 17. Acompound of Claim 12 wherein in the three R terms T is PfOJR'OH, where 5 R 1 is C.-C 5 alkyl, and n is 1. 18. Acompoundof Claim 1 wherein X and Yare H. 19. Acompound of Claim 1 wherein nis 1. 20. A compound of Claim 1 wherein A, Q and Z are CH. 21. Acompound of Claim 1 wherein when A, Q and ZareCH, in at least one of 0 the Rterms T is otherthan PfOJR'OH where R 1 is OH. 22. A compound of Claim 1 wherein Q, A and Z are CH; and in the three R terms X, Y and n are defined as in Claim 1 , and one T term is where R 2 and R 4 are defined as in Claim 1, and the other two T terms are defined as in Claim 1. 23. A compound of Claim 22 wherein n is 1. 24. A compound of Claim 22 wherein Q, A and Z are CH; and in two R terms X and Y are H; in one R term X is C0 2 CH 3 and Y is H; n is 1 ; and one T term is and named as 3,6,9, 15-tetraazabicycl o[9.3.1 Jpentadeca- 1 ( 15), 1 1 J 3-triene-3[(4- nitrophenyl)methyl acetate]-6,9-methylenediethylphosphonate. 25. A compound of Claim 22 wherein in the R term that contains a T moiety which has the R 4 group present, also has one of X or Y of that R term equal to COOH. 26. A compound of Claim 22 wherein in the two R terms not containing an R 4 term, all remaining X and Y terms are H. 27. A compound of Claim 26 wherein in the two R terms not containing an R 4 term, both T terms are P(0)R'OH, where R 1 is defined as in Claim 1 and is the same moiety. 28. A compound of Claim 26 wherein in the two R terms not containing an R 4 term, one T term is a COOH and the other T term is PfOJR'OH, where R 1 is defined as in Claim 1. 29. A compound of Claim 1 wherein X and Y are H; T is COOH where: R 1 is -OH, C.-C 5 alkyl or-0-(C.-C 3 alkyl). 30. A compound of Claim 29 wherein Q and Z are CH. 31. A compound of Claim 30 wherein A is C-OR 3 , C-OR 8 , where R 3 and R 8 are defined as in Claim 1 , or where R 4 is defined as in Claim 1. 32. A compound of Claim 29 wherein A is CH, and one of Q or Z is CH and the other is C-C(0)-R 6 , where R 6 is defined as in Claim 1. 33. A compound of Claim 32 wherein R 6 is NHR 7 , where R 7 is a biologically active material. 34. A compound of Claim 1 wherein one of A, Q or Z is N + -R 5 X " , where R 5 and x * are defined as in Claim 1 ; and in one R term, the T moiety is P(0)R'OH, where R' is C.-C 5 alkyl or -0-(C.-C 5 alkyl); and in the other two R terms, the T moiety is P(0)R'OH, where R 1 is C.-C 5 alkyl, -0-(C.-C 5 alkyl) or COOH; and all X and Y terms are H. 35. A compound of Claim 34 wherein in all three R terms, the T moiety is P(0)R 1 OH, where R' is C.-C 5 alkyl or -0-(C.-C 5 alkyl). 36. A complex which comprises a bicyclopolyazamacrocyclophosphonic acid compound as claimed in any one of Claims 1-35; complexed with a metal ion selected from Gd +3 , Mn +2 or Fe +3 . 37. A complex of Claim 36 wherein three R terms have T equal to P(0)R 1 OH where R 1 is OH; and X and Y are H, and named as 3,6,9,15-tetraazabicyclo[9.3.1 Jpentadeca- 1(15)J 1 J3-triene-3,6,9-trimethylenephosphonic acid. 38. A complex as claimed in Claim 36 or 37 wherein the metal is Gd *3 . 39. A conjugate comprising a bicyclopolyazamacrocyclophosphonic acid compound as claimed in any one of Claims 1-35, with the proviso that one of R 4 , R 7 or Rδ must be present; complexed with a metal ion selected from Gd +3 , Mn +2 or Fe +3 ; and covalently attached to a biologically active material. 40. A conjugate of Claim 39 wherein the biologically active material is a dextran, a peptide or polypeptide, a molecule that has specific affinity for a receptor, or an antibody or antibody fragment. 41. A conjugate of Claim 40 wherein the antibody or antibody fragment is a monoclonal anti body or fragment thereof. 42. A conjugate of Claim 39 wherein A is CH, and one of Q or Z is CH and the other is C-C(0)-R 6 , where R 6 is NHR 7 , where R 7 is a biologically active material. 43. A conjugate of Claim 42 wherein three R terms have T equal to P(0)R 1 OH where R 1 is OH; and X and Y are H or pharmaceutically-acceptable salts thereof. 44. A conjugate of any one of Claims 30-43 wherein the metal ion is Gd * 3 . 45. A pharmaceutical formulation comprising a complex of Claim 36 with a pharmaceutically-acceptable carrier. 46. A pharmaceutical formulation comprising a conjugate as claimed in Claim 39 with a pharmaceutically-acceptable carrier. 47. A method for the diagnosis of a disease state in an animal which comprises administering to said animal an effective amount of the formulation of Claim 45. 48. A method for the diagnosis of a disease state in an animal which comprises administering to said animal an effective amount of the formulation of Claim 46. 49. The use of a complex of Claim 36 as a diagnostic agent. 50. The use of a conjugate of Claim 39 as a diagnostic agent. 51. A process for preparing a complex as claimed in Claim 36 which comprises reacting a bicyclopolyazamacrocyclophosphonic acid compound as claimed in Claim 1 with a metal ion selected from Gd +3 , Mn +2 or Fe +3 under aqueous conditions at a pH from 5 to 7. 52. The process of Claim 51 wherein the bicyclopolyazamacrocyclophosphonic acid compound is 3,6,9,15-tetraazabicyclo[9.3.1]pentadeca-1(15), 1 1 ,13-triene-3,6,9-tri- methylenephosphonic acid. 53. A process for preparing a bicyclopolyazamacrocyclophosphonic acid compound as claimed in Claim 1 which comprises reacting: (A) a compound of the Formula (I) wherein at least 1 R group is H, with a phosphonating agent; or (B) a compound of Formula (I) wherein Q, A or Z has a protecting group present, after step (A), removing the blocking group by catalytic hydrogenation or acid. 54. The process of Claim 53 wherein the phosphonating agent has the formula P(OR) 3 where R is defined as in Claim 1. 55. The process of Claim 53 wherein the phosphonating agent has the formula P(OR) 3 where R is defined as in Claim 1 , and formaldehyde in a solvent.

Inventors: GARLICH JOSEPH R, KIEFER GARRY E, SIMON JAIME, GARLICH, JOSEPH, R., KIEFER, GARRY, E., SIMON, JAIME
Applicants: DOW CHEMICAL CO, THE DOW CHEMICAL COMPANY
Application year: 1993
Main classification: C07F9
IPC codes: A61K31, A61K38, A61K39, A61K49, A61K51, C07F9, C07F13, C07F15, C07K14, C07K16