Indian Patents. 201757:"TRIAZATRINAPHTHYRINS AND THE USE LHEREOF"

Title of Invention	"TRIAZATRINAPHTHYRINS AND THE USE LHEREOF"
Abstract	A novel class of macro-cycles, termed triazatrinaphtbyrins, is disclosed having general Formula (I) or a solvate, hydrate, ester or salt thereof; wherein R1, R2, R3, Ra, Ra' ,Ra", Rh, Rh' Rh", Rc, Rc', Rc", Rd, Rd" and Rd" are defined in the specification. The macrocycles are useful in the extraction of transition metals, in particular in the extraction of lanthanides.

Full Text	WO 01/46193 PCT/US00/34911 Triazatrinaphthyrins and the Use Thereof Background of the Invention Field of the Invention The present invention relates to macrocycles having three naphthyridine 5 subunits and salts and metal complexes thereof; to a process for the preparation of these macrocycles, their salts and complexes; and to the use of compositions of these macrocycles for extracting a transition metal and a method for extracting a transition metal using the composition. Related Art 10 The transition metals include the nine metals of Group VIII of the periodic table, as representative examples thereof, and the lanthanide and actinide metals. The transition metals further include the metals called rare metals, noble metals, and heavy metals. Specific examples thereof include iron (Fe), cobalt (Co), nickel (Ni), ruthenium (Ru), rhodium (Rh), palladium (Pd), osmium (Os), indium 15 (Ir), platinum (Pt), titanium (Ti)t vanadium (V), chromium (Cr), manganese (Mn), copper (Cu), zinc (Zn), yttrium (Y), zirconium (Zr), niobium (Nb), molybdenum (Mo), silver (Ag), cadmium (Cd), lanthanum (La), cerium (Ca), neodymium (Nd), samarium (Sm), europium (Eu), gadolinium (Gd), terbium (Tb), holmium (Ho), erbium (Er), thulium (Tm), ytterbium (Yb), lutetium (Lu), hafnium (Hf)> tantalum 20 (Ta), tungsten (W), gold (Au), mercury (Hg), uranium (U), and plutonium (Pu). These transition metals are used not only in catalysts and iron/steels but also in a wide variety of other applications such as hydrogen-absorbing alloys, batteries, magnets, and superconductive materials. These metals are desired to be recovered from so-called secondary resources from the standpoint of stable 25 supply. Furthermore, it in necessary to treat industrial drainage and the like to remove the metals contained therein in slight amounts. Thus, the establishment of an efficient metal recovery technique is an important subject also from the standpoint of environmental protection. WO 01/46193 PCT/US00/34911 -2- One of the elemental techniques for the recovery and purification of transition metals is the solvent extraction method. The solvent extraction method has conventionally employed an acid, basic, or neutral extracting agent according to the composition of the solution to be treated. Besides being used alone, 5 transition metals have recently come to be used as composites and similar materials such as alloys and mixtures. It is hence thought that the solvent extraction method comes to be utilized increasingly. There is a desire for an extracting agent which has higher extraction capacity, higher extraction rate, and higher selectivity and is harmless and 10 inexpensive. Summary of the Invention An object of the present invention is to provide an extracting agent for a transition metal which has a novel structure entirely different from the structure of any known extracting agent for a transition metal and has excellent extracting 15 performance. Another object of the present invention is to provide a method for extracting a transition metal with the extracting agent. The present invention addresses these and other shortcomings in the prior art by providing macrocyclic compounds for use in specific metal ion binding. 20 The invention concerns a class of novel macrocycles, termed triazatrinaphthyrins, and their metal complexes and salts. In a general and overall sense, the novel triazatrinaphthyrin compounds of the present invention include those with structures in accordance with general Formula /: WO 01/46193 3_ PCT/USOO/34911 or a solvate, hydrate, ester or salt thereof; wherein R1-R3 and Ra, Ra', Ra ,Rb, Rb', Rb", Rc, Rc', Rc' , Rd, Rd' and Rd" are as defined below. These and other objects of the present invention are accomplished by a 5 composition for extracting a transition metal .which comprises as an active ingredient a triazatrinaphthyrin or a salt thereof- Furthermore, these and other objects of the present invention are accomplished by a method for extracting a transition metal which comprises extracting a transition metal with the above-described composition for extracting 10 a transition metal. Brief Description of the Accompanying Figures FIG. 1 depicts a vertical Abderhalden apparatus for use in the synthesis of the triazatrinaphthyrin macrocycles of the present invention. Detailed Description of the Preferred Embodiments 15 The novel triazatrinaphthyrin compounds of the present invention include those with structures in accordance with general Formula /: WO 01/46193 PCT/USOO/34911 -4- or a solvate, hydrate, ester or salt thereof; wherein: R1 , R2 and R3 are each independently selected from hydrogen, alkyl, cycloalkyl, aryl, aralkyl, heterocycle and formyl, any of which is optionally 5 substituted; Ra, Ra', Ra" Rb, Rb', Rb", Rc, Rc', Rc", Rd, Rd' and Rd" are each independently selected from hydrogen, alkyl, cycloalkyl, hydroxyalkyl, alkoxyalkyl, aryloxyalkyl, alkenyl, alkynyl, aryl, acyl, heterocycloalkyl, sulfonyl, alkylsulfonyl, arylsulfonyl, aminosulfonyl, nitroalkyl, aminoalkyl, monoalkylaminoalkyl, 10 di alkyl aminoalkyl, carboxy, amino, nitro, cyano, acyl, aminocarbonyl, hydroxy, alkoxy, aryloxy, aminocarbonyloxy, carbonylamino, sulfonylamino or aralkyl, any of which is optionally substituted. When a group is optionally substituted, the optional substituents can be one or more non-hydrogen substituents, provided that the resulting compound is 15 stable. Values of optional substituents are halogen, hydroxy, alkyl, cycloalkyl, aralkyl, aryl, thiol, amino, mono alkyl amino, dialkylamino, formylamino, aminoiminomethyl, acylamino, aminoacyl, mono- or di- alkylaminocarbonyl, thiocarbonylamino, thioacylamino, aminothiocarbonyl, alkoxy, aryloxy, aminocarbonyloxy, mono- or di-alkylaminocarbonyloxy, mono- or 20 diarylaminocarbonyloxy, mono- or diaralkylaminocarbonyloxy, alkylsulfonyl, arylsulfonyl, aralkylsulfonyl, alkylsulfonylamino, arylsulfonylamino, aralkylsulfonylamino, alkoxycarbonylamino, aralkoxycarbonylamino, WO 01/46193 PCT/US00/34911 aryloxycarbonylamino, mono- or di- alkylaminothiocarbonyl, aralkoxy, carboxy, carboxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, nitro, cyano, trifluoromethyl, alkylthio and arylthio. Preferred values of optional substituents on alkyl and cycloalkyl groups 5 are chloro, hydroxy, amino, mono(C1-4)alkylamino, di(C1-4)alkylamino, formylamino, C2-6 acylamino, aminocarbonyl, C2_8 aminoacyl, C1-6 alkoxy, C6-14 aryloxy, carboxy, carboxy(C1-6)alkyl, C2-8 alkoxycarbonyl, nitro, cyano, trifluoromethyl, C1-6 alkylthio, C6-I4 arylthio, C,1-6 alkylsulfonylamino, C7-15 aralkylsulfonylamino, C6-.10 arylsulfonylamino, mono- or di(C1_ 10 6)alkylaminocarbonyloxy, mono- or di- (C6_l0)arylaminocarbonyloxy, mono- or di(C7.i5)aralkylcarbonyloxy, C1-6 alkoxycarbonylamino, C7-C15 aralkoxycarbonylamino, and C6-C10 aryloxycarbonylamino. Preferred values of optional substituents on aryl-containing and heterocyclic-containing groups include chloro, hydroxy, amino, mono(C1-4) 15 alkylamino, di(C1-4)alkylamino, formylamino, C2-6 acylamino, aminocarbonyl, C2-8 aminoacyl, C3.7 cycloalkyl, C1-6 alkyl, Cl-6 alkoxy, C6-14 aryloxy, carboxy, carboxy(C1-6)alkyl, C2_8 alkoxycarbonyl, nitro, cyano, trifluoromethyl, C1-6 alkylthio, C6_14 arylthio, C6-l4 aryl, phenyl (further optionally substituted by one, two or three of chloro, hydroxy, C1-4 alkyl, C1-4 alkoxy, amino or carboxy), 20 tetrazolyl (further optionally substituted by one, two or three of chloro, hydroxy, C1-4 alkyl, C1-4 alkoxy, amino or carboxy), thienyl (further optionally substituted by one, two or three of chloro, hydroxy, C1-4 alkyl, C14 alkoxy, amino or carboxy), 3,4-methylenedioxy, 3,4-ethylenedioxy, 3,4-propylenedioxy, C,^ alkylsulfonylamino, C7-15 aralkylsulfonylamino, C1-6 arylsulfonylamino, C1-6 25 alkylsulfonyl, C 6-10 arylsulfonyl, mono- or di(C1-6)alkylaminocarbonyloxy, mono- or di- C6-10 arylaminocarbonyloxy, mono- or di-(C7-15 ) aralkylcarbonyloxy, C1-6 alkoxycarbonylamino, C7-C15 aralkoxycarbonylamino, C6-C10 aryloxycarbonylamino, C2-6 thioacylamino, aminothiocarbonyl, and C2-.8 aminothioacyl. 30 Preferred values of R1, R2 and R3 are hydrogen. WO 01/46193 PCT/US00/34911 -6- Preferred values of Rb, Rb', Rb", Rc, Rc' and Rc" are hydrogen, C1_6 alkyl, C3-8 cycloalkyl, sulfonyl, and C6.-14 aryl, any of which is optionally substituted. Preferred values of Ra, Ra', Ra", Rd, Rd' and Rd" are hydrogen, C1-6 alkyl, sulfonyl and C6-14 ar(C1-6)alkyl, any of which is optionally substituted. 5 Methods for the preparation of various 3-, 4-, 5- and 6-substituted naphthyridines as starting materials for the preparation of the correspondingly substituted triazatrinaphthyrins are described herein. Functional group manipulation of the 3-, 4-, 5- and 6-positions (Ra, Ra', Ra", Rb, Rb", Rb" Rc, Rc', Rc" Rd, Rd' and Rd") is possible after macrocycle formation, or the appropriately 10 substituted naphthyridines may be used directly, depending upon the particular triazatrinaphthyrin desired. Triazatrinaphthyrin itself (wherein R'-R3 and Ra, Ra', Ra" Rb, Rb, Rb", Rc, Rc', Rc" Rd, Rd' and Rd" are each hydrogen) is a macrocycle which is generally characterized by the presence of three 2-amino-l,8-naphthyridine subunits 15 contained within a macrocyclic framework and by emission bands that are red shifted as compared to those of porphyrins. Triazatrinaphthyrin and its substituted derivatives are characterized by the ability to form complexes with metal ions. Triazatrinaphthyrin and its substituted derivatives are further 20 characterized by the ability to undergo facile protonation at one or more naphthyridine nitrogens and/or bridging "meso" nitrogens. It is understood that the triazatrinaphthyrin compounds of the present invention may be either singly or doubly protonated, and in certain embodiments triply or four-fold protonated. The term "alkyl" as employed herein by itself or as part of another group 25 refers to both straight and branched chain radicals of up to 12 carbons, such as methyl, ethyl, propyl, isopropyl, butyl, t-butyl, isobutyl, pentyl, hexyl, isohexyl, heptyl, 4,4-dimethylpentyl, octyl, 2,2,4-trimethylpentyl, nonyl, decyl, undecyl, dodecyl. The term "alkenyl" is used herein to mean a straight or branched chain 30 radical of 2-20 carbon atoms, wherein there is at least one double bond between two of the carbon atoms in the chain including, but not limited to, ethenyl, 1- WO 01/46193 PCT/US00/34911 -7- propenyl, 2-propenyl, 2-methyl-l-propenyl, 1-butenyl, 2-butenyl, and the like. Preferably, the alkenyl chain is 2 to 10 carbon atoms in length, more preferably, 2 to 8 carbon atoms in length most preferably from 2 to 4 carbon atoms in length. The term "alkynyl" is used herein to mean a straight or branched chain 5 radical of 2-20 carbon atoms, wherein there is at least one triple bond between two of the carbon atoms in the chain, including, but not limited to, acetylene, 1-propylene, 2-propylene, and the like. Preferably, the alkynyl chain is 2 to 10 carbon atoms in length, more preferably, 2 to 8 carbon atoms in length, most preferably from 2 to 4 carbon atoms in length. 10 In all instances herein where there is an alkenyl or alkynyl moiety as a substituent group, the unsaturated linkage, i.e., the vinylene or acetylene linkage is preferably not directly attached to a nitrogen, oxygen or sulfur moiety. The term "alkylthio" as employed herein by itself or as part of another group refers to a straight or branched chain radical of 1 to 20 carbon atoms, 15 bonded to a sulfur atom, including, but not limited to, methylthio, ethylthio, n- propylthio, isopropylthio, and the like. Preferably the alkylthio chain is 1 to 10 carbon atoms in length, more preferably 1 to 8 carbon atoms in length. The term "alkoxy" as employed herein by itself or as part of another group refers to a straight or branched chain radical of 1 to 20 carbon atoms, bonded to 20 an oxygen atom, including, but not limited to, methoxy, ethoxy, rc-propoxy, isopropoxy, and the like. Preferably the alkoxy chain is 1 to 10 carbon atoms in length, more preferably 1 to 8 carbon atoms in length. The term "cycloalkyl" as employed herein by itself or as part of another group refers to cycloalkyl groups containing 3 to 9 carbon atoms. Typical 25 examples are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and cyclononyl. The term "halogen" or "halo"as employed herein by itself or as part of another group refers to chlorine, bromine, fluorine or iodine with chlorine being preferred. 30 The term "acyl" as employed herein by itself or as part of another group refers to the group -C(O)Rg where Rg is alkyl, alkenyl, alkynyl, aryl, aralkyl, WO 01/46193 PCT/US00/34911 aralkenyl, heteroaryl, heteroarylalkyl or heteroarylalkenyl. Preferred acyl groups are alkanoyl, aralkanoyl and aroyl groups (-C(O)Rg where R8 is C,.B alky], C6.10 aryI(C1-.4)alkyl or C6.l0 aryl). The term "thioacyl" as employed herein by itself or as part of another 5 group refers to the group -C(S)Rg where R8 is alkyl, alkenyl, alkynyl, aryl, aralkyl, aralkenyl, heteroaryl, heteroarylalkyl or heteroarylalkenyl, preferably C,_8 alkyl. The term "thiocarbonyl" as employed herein by itself or as part of another group refers to the group -C(S)-. The term "monoalkylamine" as employed herein by itself or as part of 10 another group refers to an amino group which is substituted with one alkyl group having from 1 to 6 carbon atoms. The term "dialkylamine" as employed herein by itself or as part of another group refers to an amino group which is substituted with two alkyl groups, each having from 1 to 6 carbon atoms 15 The term "aryl" as employed herein by itself or as part of another group refers to monocyclic or bicyclic aromatic groups containing from 6 to 14 carbons in the ring portion, preferably 6-10 carbons in the ring portion, such as phenyl, naphthyl or tetrahydronaphthyl. The term "aralkyl" or "arylalkyl" as employed herein by itself or as part 20 of another group refers to C1_6alkyl groups as discussed above having an aryl substituent, such as benzyl, phenylethyl or 2-naphthylmethyl. The terms "heterocyclic," "heterocyclo" or "heterocycle" as employed herein by themselves or as part of larger groups refers to a saturated or wholly or partially unsaturated 3-7 membered monocyclic, or 7-10 membered bicyclic ring 25 system, which consists of carbon atoms and from one to four heteroatoms independently selected from the group consisting of O, N, and S, wherein the nitrogen and sulfur heteroatoms can be optionally oxidized, the nitrogen can be optionally quaternized, and including any bicyclic group in which any of the above-defined heterocyclic rings is fused to a benzene ring, and wherein the 30 heterocyclic ring can be substituted on carbon or on a nitrogen atom if the resulting compound is stable. Especially useful are rings containing one oxygen WO 01/46193 PCT/US00/34911 or sulfur, one to three nitrogen atoms, or one oxygen or sulfur combined with one or two nitrogen atoms. Examples of such heterocyclic groups include piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolodinyl, 2- oxoazepinyl, azepinyl, pyrrolyl, 4-piperidonyl, pyrrolidinyl, pyrazolyl, 5 pyrazolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazolyl, oxazolidinyl, isoxazolyl, isoxazolidinyl, morpholinyl, thiazolyl, thiazolidinyl, isothiazolyl, quinuclidinyl, isothiazolidinyl, indolyl, indanyl, quinolinyl, isoquinolinyl, benzimidazolyl, thiadiazoyl, benzopyranyl, benzothiazolyl, benzoxazolyl, furyl, tetrahydrofuryl, 10 tetrahydropyranyl, thienyl, benzothienyl, thiamorpholinyl, thiamorpholinyl sulfoxide, thiamorpholinyl sulfone, and oxadiazolyl. Morpholino is the same as morpholinyl. The term "heteroatom" is used herein to mean an oxygen atom ("O"), a sulfur atom ("S") or a nitrogen atom ("N"). It will be recognized that when the 15 heteroatom is nitrogen, it may form an NRyRz moiety, wherein Ry and Rz are, independently from one another, hydrogen or C, to C8 alkyl, or together with the nitrogen to which they are bound, form a saturated or unsaturated 5-, 6-, or 7-membered ring. The term "heteroaryl" as employed herein refers to groups having 5 to 14 20 ring atoms; 6,10 or 14 n electrons shared in a cyclic array; and containing carbon atoms and 1, 2 or 3 oxygen, nitrogen or sulfur heteroatoms (where examples of heteroaryl groups are: thienyl, benzo[b] thienyl, naphtho[2,3-b]thienyl, thianthrenyl, furyl, pyranyl, isobenzofuranyl, benzoxazolyl, chromenyl, xanthenyl, phenoxathiinyl, 2ff-pyrrolyl, pyrrolyl, imidazolyl, pyrazolyl, pyridyl, 25 pyrazinyl, pyrimidinyl, pyridazinyl, indolizinyl, isoindolyl, 3//-indolyl, indolyl, indazolyl, purinyl, 4tf-quinolizinyl, isoquinolyl, quinolyl, phthalazinyl, naphthyridinyl, quinazolinyl, cinnolinyl, pteridinyl, 4octf-carbazolyl, carbazolyl, p-carbolinyl, phenanthridinyl, acridinyl, perimidinyl, phenanthrolinyl, phenazinyl, isothiazolyl, phenothiazinyl, isoxazolyl, furazanyl and phenoxazinyl groups). 30 The term "substituted", as used herein, means that one or more hydrogens of the designated moiety are replaced with a selection from the indicated group, WO 01/46193 PCT/US00/34911 provided that no atom's normal valency is exceeded, and that the substitution results in a stable compound. When a substituent is keto (i.e., =O), then 2 hydrogens attached to an atom of the moiety are replaced. By "stable compound" or "stable formula" is meant herein a compound 5 that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture and formulation into an efficacious therapeutic or diagnostic agent. The triazatrinaphthyrin macrocycles of the present invention may be protonated and exist in the form of a salt. The terms "salt", "acid addition salt" or 10 "pharmaceutically acceptable salt" are intended to include all acceptable salts. Examples of acid salts are hydrochloric, hydrobromic, hydrofluoric, perchloric, nitric, sulfuric, phosphoric, formic, acetic, trifluoroacetic, propionic, maleic, succinic, malonic, methane sulfonic and the like. A triazatrinaphthyrin macrocycle of the present invention in the form of a salt is characterized by the 15 pronation of one of more nitrogen atoms. The complete salt consists of the monoprotonated or multiprotonated macrocycle and its associated anion(s). Macrocycle Synthesis The preferred starting material for the preparation of the triazatrinaphthyrin macrocycles of the present invention is the appropriately 20 substituted 2,7-diamino-1,8-naphthyridine. Scheme 1 illustrates the synthetic sequence for the preparation of various 2,7-diamino-1,8-naphthyridines (5a). As shown, this is accomplished by reacting the corresponding 2-amino-7-chloro-l,8-naphthyridine (4) or 2,7-dichloro-l,8-naphthyridine (7) with anhydrous ammonia or other amine. The 2-amino-7- 25 chloro-l,8-naphthyridines (4) can be prepared according to the method of Carboni, S. etal, Gazz. Chim. hah 96(11): 1456-1459 (1966), herein incorporated by reference in its entirety, which begins with the formation of 2-amino-7-hydroxy-l,8-naphthyridine (3) from the appropriately substituted 2,6-diaminopyridine (1) and p-ketoester (2). Those of skill in the art of organic WO 01/46193 PCT/US00/34911 synthesis will appreciate the availability of alternate reagents and conditions for affecting the conversions outlined in Scheme 1. 5 2,7-diamino-l,8-naphthyridines ((5), R1" = RIV=H) maybe functionalized to provide the desired Ra, Ra', Ra", Rb, Rb', Rb", Rc, Rc', Rc", Rd, Rd' and Rd" groups of Formula /. For example, as shown in Scheme 2 below, protection of the 2- and 7-amino groups with a suitable protecting group and subsequent treatment with base generates one or more nucleophilic carbon atoms on the naphthyridine ring 10 which can react with the appropriate electrophile (e.g., alkyl halides, epoxides, anhydrides, sulfonate esters and the like) to arrive at a functionalized 2,7-diaminonaphthyridine for use in the subsequent macrocycle forming reaction. WO 01/46193 PCI -12- For certain Ra, Ra', Ra", Rb, Rb', Rb", Rc, Rc', Rc", Rd, Rd' andRd" substituents of Formula I which are incompatible with the reaction conditions of macrocycle 5 formation, and which cannot be prepared by derivatization of other groups, functional group manipulation of those positions may be carried out after macrocycle formation. The synthetic strategies outlined herein allow for the formation of triazatrinaphthyrins wherein Ra, Ra', Ra", Rd, Rd' and Rd" of Formula / are 10 hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl, aryloxyalkyl, alkenyl, alkynyl, acyl, heterocycloalkyl, alkylsulfonyl, arylsulfonyl, nitroalkyl, aminoalkyl, monoalkylaminoalkyl, dialkylaminoalkyl or aralkyl, any of which is optionally substituted; and Rb Rb', Rb", Rc, Rc', and Rc" of Formula / are each independently selected from hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, aralkyl, carboxy, 15 amino, nitro, cyano, acyl, aminocarbonyl, alkylsulfonyl, arylsulfonyl, aminosulfonyl, hydroxy, alkoxy, aryloxy, aminocarbonyloxy, carbonylamino, sulfonylamino, any of which is optionally substituted. WO 01/46193 PCT/US00/34911 Scheme 3 illustrates the synthesis of the parent triazatrinaphthyrin (wherein Ra, Ra,' Ra", Rb, Rb', Rb", Rc, Rc', Rc", Rd, Rd' and Rd" of Formula/ are each hydrogen). The macrocycle forming reaction is carried out in a vertical Abderhalden apparatus (see Figure 1) or in a tube furnace, the latter providing 5 better temperature control. In general, the macrocycle forming reaction is characterized by the treatment of a 2,7-diamino-1,8-naphthyridine with hydrogen halide gas at a temperature sufficient to cause melting of the 2,7-diamino-l,8-naphthyridine in 1 atmosphere of hydrogen halide gas. While not intending to be limited to any mechanistic explanation, the reaction is believed to proceed by 10 elevation ofahydrohalidesalt of2,7-diamino-l,8-naphthyridine to a temperature sufficient to cause amine extrusion and triazatrinaphthyrin formation. The details of an embodiment of the synthesis as carried out in the Abderhalden apparatus are outline in Example 1. It is to be understood that the macrocycle-forming reaction can be carried 15 out with a single 2,7-diamino- 1,8-naphthyridine or with a mixture of 2,7- diamino- 1,8-naphthyridines. When the macrocycle-forming reaction is carried out with a mixture of 2,7-diamino-1,8-naphthyridines, a mixture of products (including various regioisomers) is obtained. One of skill in the art will appreciate various chromatographic media and solvent systems capable of 20 separating a mixture of triazatrinaphthyrins and isolating the desired compound from the mixture. Typical chromatographic media include various mesh sizes of silica gel or alumina and typical solvent systems include mixtures of polar and non-polar solvents such as CHC13/CH3OH, CH2C12/CH3OH, and others known in the art of chrornatography. 25 An alternative embodiment of the process for forming triazatrinaphthyrins involves the use of a hydrohalide salt of an aromatic amine or a mixture of aromatic amines (including, but not limited to, pyridinium hydrochloride, quinoline hydrochloride or 4-(3-phenylpropyl)pyridine hydrochloride) as a solvent in which a 2,7-diamino-l,8-naphthyridine is dissolved and the 30 temperature elevated sufficiently to cause melting of the solvent and amine WO 01/46193 PCT/US00/34911 -14- extrusion and triazatrinaphthyrin formation. Certain solvents, such as pyridinium hydrochloride, when heated to near its boiling point of 222 °C, facilitate the formation of triazatrinapthyrin in 1 atmosphere of hydrogen chloride at temperatures well below 300 °C. 5 At sufficiently elevated temperatures, the use of hydrogen chloride or a hydrohalide salt may not be necessary to effect formation of the triazatrinapthyrin. Specifically, the di-n-propyl-diaminonaphthyriine outlined in Scheme 2, when heated rapidly and briefly to its melting point of about 340 °C in a sealed tube, spontaneously forms the corresponding hexapropyl 10 triazatrinapthyrin in good yield. Accordingly, the present invention also encompasses a process for forming a triazatrinaphthyrin by heating a 2,7-diamino-l,8-naphthyridine at, or above, its melting temperature to yield the desired triazatrinaphthyrin. WO 01/46193 PCT/US00/34911 Metalation/Addition of Radioisotopes The triazatrinaphthyrin compounds of the present invention include those where the triazatrinaphthyrin is complexed with certain metals for use as a transition metal complexing agent, or simply as a convenient form of the 5 compound. Examples of metals which are appropriate include paramagnetic ions of elements such as Gd, In, Eu, Dy, Pr, Pa, Cr, Co, Fe, Cu, Ni, Ti, and V, preferably Gd or Eu. Complex formation is typically carried out in a polar solvent, including but not limited to, water, isopropanol, ethanol, methanol, acetone, DMF, DMSO, acetonitrile and the like. Solvent systems including a 10 mixture of solvents and/or aqueous solvent mixtures are also contemplated. Typically, the metal ion in the form of its halide or acetate salt is used in the complex forming reaction. An exemplary complex forming reaction is described in Example 2. Protonated Macrocycles 15 Triazatrinaphthyrins undergo facile protonation at one or more naphthyridine nitrogens or at one or more apical (or "meso") nitrogens. Typically, a triazatrinaphthyrin is contacted with an acid selected from hydrochloric, hydrobromic, hydrofluoric, perchloric, nitric, sulfuric, phosphoric, formic, acetic, trifluoroacetic, propionic, maleic, succinic, malonic, and methane 20 sulfonic in an aqueous solution. The resulting singly or multi-protonated macrocycle is associated with one or more negatively charged counterions, depending on the acid used to protonate the macrocycle. Example 1 11,22,33- Triazatrinaphthyrin 25 a. 2,7-Diamino-l,8-naphthyridine. 2-Amino-7-chloro-l,8- naphthyridine (50 grams, 0.28 moles), prepared by the method of Carboni, S. et al, Gazz. Chim. Ital. 96(11): 1456-1459 (1966), was loaded into a 2 liter Parr WO 01/46193 PCT/US00/34911 -16- bomb and charged with liquid anhydrous ammonia (500 ml). The bomb was sealed, brought to a pressure of 1200 PSI, and maintained at this pressure for 14 hours. The bomb was thencooled to room temperature, the ammonia vented, and the bomb contents extracted, first with 1.5 liters of saturated aqueous ammonia, 5 then with 500 ml of saturated aqueous ammonia. These clear yellow liquid extracts were combined and concentrated on the rotary evaporator to a volume of about 250 ml, yielding a flocculent precipitate which was collected and dried to give the product 2,7-diamino-l,8-naphthyridine (26 g, 162 mmol, 58%), mp 311°C (lit. mp = 222-223 °C; Collin, J.-P., et ai, Inorg Chim. Acta 201:29-34 10 (1992)). lHNMR(DMSO-d6):67.76(d,7=9Hz,2H,C//),71.4(br.s.)4H,NH2), 6.50(d,J=9Hz,CH). l3CNMR: 6 160.7,144.4,140.2,109.9,108.6. MS m/e 160 (100%), 133 (25%), 105 (9%). HRMS calc'd for C8H8N4: m/e= 160.074896. Found: m/e= 160.074984. UV-visible 2max (log e) (25% aqueous EtOH): 352(4.07). Emission 2max (arbitrary units) (25% aq.. EtOH/IPA):, 407(0.48), 15 493(1.00). b. 11,22,33-Triazatrinaphthyrin. A custom-built vertical Aberhalden apparatus (see Figure 1) was charged with 2,7-diamino-l,8-naphthyridine (12 grams) and capped with a stoppered top leading to a manifold capable of replacing a vacuum with 1 atmosphere of anhydrous hydrogen chloride gas. The 20 diaminonaphthyridine was held under vacuum in the inner chamber of the Aberhalden vessel until such time as condensing vapors of sulfuric acid (bp=300 °C) began to bathe the outside of the inner chamber and the diaminonaphthyridine began to change color from the heat. The vacuum was then promptly replaced with 1 atm of anhydrous hydrogen chloride. The 25 diaminonaphthyridine quickly melted, darkened, and began to bubble. After 40 minutes the darkened reaction mass had completely resolidified, and heating was continued for an additional 20 minutes. The apparatus was allowed to cool, and the crude product was removed from the vessel and ground to a powder. This whole process was repeated and the two batches were combined and washed as 30 follows: The dark powder was stirred with 200 ml concentrated aqueous WO 01/46193 PCT/US00/34911 ammonia for 30 minutes, then filtered, and the moist solid so obtained was washed two more times by stirring for 1 hour with 500 ml warm ethanol saturated with ammonia vapor. The remaining solid material (dry weight 19 grams) was stirred for 12 hours in 250 ml of glacial acetic acid held at 60 °C. The resultant 5 dark solution was filtered through a medium glass fritted funnel and concentrated to dryness on a rotary evaporator. The residue so obtained was dried in vacuo at 100 °C for 24 h to give the product as a dark purple solid (16.5 g, 38.5 mmole, 77%). 'H NMR (CF3COOD): 6 7.98 (d, J=9.3 Hz, 2H, CH), 6.95 (d, J=93 Hz, CH). 13CNMR(CF3COOD): 6 155.5, 144.8, 144.3, 118.1, 116.3. MS m/e 429 10 (100%), 214 (10%). HRMS calc'd for C24H9: m/e= 429.1450. Found: m/e=429.1449. UV-visible 2max (log e) (HOAc): 340 (4.78), 356 (4.96), 406 (3.51), 480-82sh (3.11). Emission 2max (arbitrary units)(sh = shoulder) (concentrated HC1): 535-542sh (0.275), 569 (1.00), 615 (0.29). Example 2 15 11,22,33~Triazatrinaphthyrin o Gd(III) Acetate A 50 mL flask is charged with 11,22,33-triazatrinaphthyrin (100 mg, 0.23 mol) and 15 mL 33% aqueous acetic acid. The clear dark solution is stirred at room temperature and Gd(III) chloride hexahydrate (75 mg, 0.20 mol) in 2 mL of water is added in one portion. Complex formation may monitored by 20 observing the characteristic changes in UV-Vis absorption, although complex formation is essentially complete within a minute. The resulting solution is evaporated under reduced pressure and washed with glacial acetic acid to remove uncomplexed triazatrinaphthyrin. The resulting complex is obtained in quantitative yield based on the amount of staring Gd(EH) chloride hexahydrate. 25 Extraction of Metals Besides the nine elements of Group VIII of the periodic table, the transition metals include the elements of Groups 3A to 7A and Groups 1B and 2B, that is, the elements ranging from scandium, having an atomic number of 21, WO 01/46193 PCT/US00/34911 -18- to zinc, having an atomic number of 30, from yttrium, having an atomic number of 39, to cadmium, having an atomic number of 48, from lanthanum, having an atomic number of 57, to mercury, having an atomic number of 80, and from actinium, having an atomic number of 89, to lawrencium, having an atomic 5 number of 103. Specifically, the transition metals include the elements of Group VIII, i.e., iron (Fe), cobalt (Co), nickel (Ni), ruthenium (Ru), rhodium (Rh), palladium (Pd), osmium (Os), iridium (IT), and platinum (Pt), and further include titanium (Ti), vanadium (V), chromium (Cr), manganese (Mn), copper (Cu), zinc (Zn), yttrium (Y), zirconium (Zr), niobium (Nb), molybdenum (Mo), silver (Ag), 10 cadmium (Cd), lanthanum (La), cerium (Ce), neodymium (Nd), samarium (Sm), europium (Eu), gadolinium (Gd), terbium (Tb), holmium (Ho), erbium (Er), thulium (Tin), ytterbium (Yb), lutetium (Lu), hafnium (Hf), tantalum (Ta), tungsten (W), gold (Au), mercury (Hg), uranium (U), and plutonium (Pu). The solution to be extracted is not particularly limited in the concentration 15 of transition metals dissolved therein. Even when the solution has a transition metal concentration as low as about 1.0 x 10"5 M, it is expected to be sufficiently extracted. Although the aqueous transition metal solution is not particularly limited in pH, it preferably has a pH below 6. As the pH of the solution is altered, the 20 degree of extraction may tend to decrease. In this case, a longer extraction period is necessary as is know in the art The extraction temperature is not particularly limited as long as it is not higher than the boiling point of the solvent used. In general, a temperature around room temperature may be used. 25 The extraction operation is conducted by bringing a solution of the triazatrinaphthyrin into contact with a solution containing transition metals dissolved therein. This contacting is accomplished by shaking, stirring, etc. Although conditions for shaking or stirring are not particularly limited, vigorous shaking or agitation is more effective in efficient extraction. Shaking may be 30 usually conducted at a frequency of about from 100 to 400 times per minute. WO 01/46193 PCT/US00/34911 An additive for accelerating the extraction (extraction accelerator) can also be used. Examples of the extraction accelerator include basic nitrogen-containing heterocyclic compounds and aromatic amino acids. Specific examples thereof 5 include nitrogen-containing heterocyclic compounds, such as pyridine, alkylpyridinas (e.g., methylpyridine, ethylpyridine), and quinoline; and amino acids containing an aromatic ring, such an tryptophan and phenylalanine. Examples of the extraction accelerator further include compounds which coordinate to transition metal ions and help the ions to associate with the 10 triazatrinaphthyrin and which thus function to heighten the rate of complex formation with transition metal ions. However, pyridine and tryptophan are preferred. Although the concentration of the extraction accelerator is not particularly limited, the amount thereof is preferably from 1 to 1,000 gram equivalents per 15 gram equivalent of the transition metal ions to be extracted. If the amount of the extraction accelerator is too small, the effect of accelerating extraction is not obtained. Conversely, if the amount thereof is too large, there is a fear that the accelerator may alter the properties of the solvent used in an organic phase. 20 The composition for extracting a transition metal of the present invention is useful for efficiently extracting transition metals, particularly lanthanides, such as gadolinium. Extraction Example Extraction of transition metals with a triazatrinaphthyrin of the present 25 invention may be carried out as follows: In the extraction experiment, 10 ml of an organic phase is prepared by dissolving triazatrinaphthyrin acetate (or other triazatrinaphtyrin macrocycle, salt or complex) in chloroform in a concentration of 5.0 x 10-4 M and placing the same in a 30-ml screw vial together with 10 ml of an acetic acid phase containing WO 01/46193 PCT/US00/34911 -20- transition metal chlorides in an amount of 1.0 x 10-4 M, and the contents are shaken for 24 hours. In determining the degree of extraction for each metal, the acetic acid phase after the shaking is analyzed with an atomic absorption photometer to determine the concentration of ions of the metal remaining therein. 5 The degree of extraction is calculated using the following equation, wherein M+tolal means the initial concentration of the metal ions and M+solulion means the found metal ion concentration in the acetic acid phase after the extraction experiment. 10 Having now fully described this invention, it will be understood to those of ordinary skill in the art that the same can be performed within a wide and equivalent range of conditions, formulations, and other parameters without affecting the scope of the invention or any embodiment thereof. All patents and publications cited herein are fully incorporated by reference herein in their 15 entirety. WO 01/46193 PCT/US00/3491! -21- Whats Claimed Is: or a solvate, hydrate, ester or salt thereof; wherein: 5 R1, R2 and R3 are each independently selected from hydrogen, alkyl, cycloalkyl, aryl, aralkyl, heterocycle and formyl, any of which is optionally substituted; Ra, Ra', Ra", Rb, Rb', Rb", Rc, Rc', Rc", Rd, Rd' and Rd" are each independently selected from hydrogen, alkyl, cycloalkyl, hydroxyalkyl, alkoxyalkyl, 10 aryloxyalkyl, alkenyl, alkynyl, aryl, acyl, heterocycloalkyl, sulfonyl, alkylsulfonyl, arylsulfonyl, aminosulfonyl, nitroalkyl, aminoalkyl, monoalkylaminoalkyl, dialkylaminoalkyl, carboxy, amino, nitro, cyano, acyl, aminocarbonyl, hydroxy, alkoxy, aryloxy, aminocarbonyloxy, carbonylamino, sulfonylamino or aralkyl, any of which is optionally substituted. 15 2. A compound of claim 1, wherein R1 , R2, R3, Ra, Ra', Ra", Rb, Rb', Rb", Rc, Rc', Rc", Rd, Rd' and Rd" are each hydrogen. 3. A compound of claim 1, wherein said optional substituents are selected from halogen, hydroxy, alkyl, cycloalkyl, aralkyl, aryl, thiol, amino, WO 01/46193 PCT/US00/34911 -22- monoalkylamino, dialkylamino, formylamino, aminoiminomethyl, acylamino, aminoacyl, mono- or di- alkylaminocarbonyl, thiocarbonylamino> thioacylamino, aminothiocarbonyl, alkoxy, aryloxy, aminocarbonyloxy, mono- or di- alkylaminocarbonyloxy, mono- or diarylaminocarbonyloxy, mono- or 5 diaralkylaminocarbonyloxy, alkylsulfonyl, arylsulfonyl, aralkylsulfonyl, alkylsulfonylamino, arylsulfonylamino, aralkylsulfonyl am in o, alkoxycarbonylamino, aralkoxycarbonylamino .aryloxycarbonylamino, mono- or di- alkylaminothiocarbonyl, aralkoxy, carboxy, carboxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, nitro, cyano, trifluoromethyl, alkylthio and arylthio. 10 4. A compound of claim 1, in the form of a monoprotonated or multiprotonated acid addition salt, wherein the acid is selected from the group consisting of hydrochloric, hydrobromic, hydrofluoric, perchloric, nitric, sulfuric, phosphoric, formic, acetic, trifluoroacetic, propionic, maleic, succinic, malonic, and methane sulfonic. 15 5. A salt comprising a singly-protonated or multi-protonated compound of claim 1 and at least one negatively charged counterion. 6. A metal complex comprising a compound of claim 1 and a metal ion. 7. A metal complex of claim 6, wherein said metal is selected from 20 the group consisting of Tc, In, Ga, Gd, Eu, Dy, Pr, Pa, Cr, Co, Fe, Cu, Ni, Ti, and V. 8. A complex according to claim 6, wherein said metal is paramagnetic. 9. A metal complex of claim 8, wherein said metal is Gd(DI) or 25 Eu(III). WO 01/46193 PCT7US00/34911 10. A method of forming a compound of Formula /: or a solvate, hydrate, ester or salt thereof; wherein: R1, R2 and R3 are each independently selected from hydrogen, alkyl, 5 cycloalkyl, aryl, aralkyl, heterocycle and formyl, any of which is optionally substituted; Ra, Ra', Ra", Rb, Rb', Rb", Rc, Rc', Rc" Rd, Rd' and Rd" are each independently selected from hydrogen, alkyl, cycloalkyl, hydroxyalkyl, alkoxyalkyl, aryloxyalkyl, alkenyl, alkynyl, aryl, acyl, heterocycloalkyl, sulfonyl, alkylsulfonyl, 10 arylsulfonyl, aminosulfonyl, nitroalkyl, aminoalkyl, monoalkylaminoalkyl, dialkylaminoalkyl, carboxy, amino, nitro, cyano, acyl, aminocarbonyl, hydroxy, alkoxy, aryloxy, aminocarbonyloxy, carbonylamino, sulfonylamino or aralkyl, any of which is optionally substituted, comprising: (a) treating a compound of Formula// 15 wherein Ra, Rb, Rc and Rd are as defined above, with hydrogen chloride gas. WO 01/46193 PCT/US00/34911 -24- 11. A method for extracting a transition metal, such as herein described, which comprise contacting a material containing the transition metal with a composition which comprises as an active extracting ingredient a compound of the following Formula: 5 or a solvate, hydrate, ester or salt thereof; wherein: R], R2 and R3 are each independently selected from hydrogen, alkyl, cycloalkyl, aryl, aralkyl, heterocycle and formyl, any of which is optionally substituted; 10 Ra, Ra' R'", R, Rb', Rb" Rc, Rc', Rc" Rd, Rd" and Rd" are each independently selected from hydrogen, alkyl, cycloalkyl, - hydroxyalkyl, alkoxyalkyl, aryloxyalkyl, alkenyl, alkynyl, aryl, acyl, heterocycloalkyl, sulfonyl, alkylsulfonyl, arylsulfonyl, aminosulfonyl, nitroalkyl, aminoalkyl, monoalkylaminoalkyl, dialkylaminoalkyl, carboxy, amino, nitro, cyano, acyl, aminocarbonyl, hydroxy, 15 alkoxy, aryloxy, aminocarbonyloxy, carbonylamino, sulfonylammo or aralkyl, any of which is optionally substituted, to extract the transition metal from the material. 12. A composition for extracting a transition metal which comprises as an active ingredient a compound of the following Formula: WO 01/46193 PCT/US00/34911 -25- or a solvate, hydrate, ester or salt thereof; wherein: R1 R2 and R3 are each independently selected from hydrogen, alkyl, cycloalkyl, aryl, aralkyl, heterocycle and fomyl, any of which is optionally 5 substituted; Ra, Ra', Ra", Rb, Rb', Rb", Rc, Rc', Rc", Rd, Rd' and Rd" are each independently selected from hydrogen, alkyl, cycloalkyl, hydroxyalkyl, alkoxyalkyl, aryloxyalkyl, alkenyl, alkynyl, aryl, acyl, heterocycloalkyl, sulfonyl, alkylsulfonyl, arylsulfonyl, aminosulfonyl, nitroalkyl, aminoalkyl, monoalkylaminoalkyl, 10 dialkylaminoalkyl, carboxy, amino, nitro, cyano, acyl, aminocarbonyl, hydroxy, alkoxy, aryloxy, aminocarbonyloxy, carbonylamino, sulfonylamino or aralkyl, any of which is optionally substituted, and an extraction accelerator selected from the group consisting of basic nitrogen-containing heterocyclic compounds and aromatic amino acids. The amount of extraction accelerator is preferably from 1 to 1,000 gram equivalents per gram equivalent of the transition metal ions to be extracted. A novel class of macro-cycles, termed triazatrinaphtbyrins, is disclosed having general Formula (I) or a solvate, hydrate, ester or salt thereof; wherein R1, R2, R3, Ra, Ra' ,Ra", Rh, Rh' Rh", Rc, Rc', Rc", Rd, Rd" and Rd" are defined in the specification. The macrocycles are useful in the extraction of transition metals, in particular in the extraction of lanthanides.

Full Text

WO 01/46193 PCT/US00/34911
Triazatrinaphthyrins and the Use Thereof
Background of the Invention
Field of the Invention
The present invention relates to macrocycles having three naphthyridine
5 subunits and salts and metal complexes thereof; to a process for the preparation
of these macrocycles, their salts and complexes; and to the use of compositions of these macrocycles for extracting a transition metal and a method for extracting a transition metal using the composition.
Related Art
10 The transition metals include the nine metals of Group VIII of the periodic
table, as representative examples thereof, and the lanthanide and actinide metals. The transition metals further include the metals called rare metals, noble metals, and heavy metals. Specific examples thereof include iron (Fe), cobalt (Co), nickel (Ni), ruthenium (Ru), rhodium (Rh), palladium (Pd), osmium (Os), indium
15 (Ir), platinum (Pt), titanium (Ti)t vanadium (V), chromium (Cr), manganese (Mn),
copper (Cu), zinc (Zn), yttrium (Y), zirconium (Zr), niobium (Nb), molybdenum (Mo), silver (Ag), cadmium (Cd), lanthanum (La), cerium (Ca), neodymium (Nd), samarium (Sm), europium (Eu), gadolinium (Gd), terbium (Tb), holmium (Ho), erbium (Er), thulium (Tm), ytterbium (Yb), lutetium (Lu), hafnium (Hf)> tantalum
20 (Ta), tungsten (W), gold (Au), mercury (Hg), uranium (U), and plutonium (Pu).
These transition metals are used not only in catalysts and iron/steels but also in a wide variety of other applications such as hydrogen-absorbing alloys, batteries, magnets, and superconductive materials. These metals are desired to be recovered from so-called secondary resources from the standpoint of stable
25 supply. Furthermore, it in necessary to treat industrial drainage and the like to
remove the metals contained therein in slight amounts. Thus, the establishment of an efficient metal recovery technique is an important subject also from the standpoint of environmental protection.

WO 01/46193 PCT/US00/34911
-2-
One of the elemental techniques for the recovery and purification of
transition metals is the solvent extraction method. The solvent extraction method
has conventionally employed an acid, basic, or neutral extracting agent according
to the composition of the solution to be treated. Besides being used alone,
5 transition metals have recently come to be used as composites and similar
materials such as alloys and mixtures. It is hence thought that the solvent extraction method comes to be utilized increasingly.
There is a desire for an extracting agent which has higher extraction
capacity, higher extraction rate, and higher selectivity and is harmless and
10 inexpensive.
Summary of the Invention
An object of the present invention is to provide an extracting agent for a
transition metal which has a novel structure entirely different from the structure
of any known extracting agent for a transition metal and has excellent extracting
15 performance.
Another object of the present invention is to provide a method for extracting a transition metal with the extracting agent.
The present invention addresses these and other shortcomings in the prior
art by providing macrocyclic compounds for use in specific metal ion binding.
20 The invention concerns a class of novel macrocycles, termed triazatrinaphthyrins,
and their metal complexes and salts. In a general and overall sense, the novel triazatrinaphthyrin compounds of the present invention include those with structures in accordance with general Formula /:

WO 01/46193 3_ PCT/USOO/34911

or a solvate, hydrate, ester or salt thereof; wherein R1-R3 and Ra, Ra', Ra ,Rb, Rb', Rb", Rc, Rc', Rc' , Rd, Rd' and Rd" are as defined below.
These and other objects of the present invention are accomplished by a
5 composition for extracting a transition metal .which comprises as an active
ingredient a triazatrinaphthyrin or a salt thereof-
Furthermore, these and other objects of the present invention are
accomplished by a method for extracting a transition metal which comprises
extracting a transition metal with the above-described composition for extracting
10 a transition metal.
Brief Description of the Accompanying Figures
FIG. 1 depicts a vertical Abderhalden apparatus for use in the synthesis of the triazatrinaphthyrin macrocycles of the present invention.
Detailed Description of the Preferred Embodiments
15 The novel triazatrinaphthyrin compounds of the present invention include
those with structures in accordance with general Formula /:

WO 01/46193 PCT/USOO/34911
-4-

or a solvate, hydrate, ester or salt thereof; wherein:
R1 , R2 and R3 are each independently selected from hydrogen, alkyl,
cycloalkyl, aryl, aralkyl, heterocycle and formyl, any of which is optionally
5 substituted;
Ra, Ra', Ra" Rb, Rb', Rb", Rc, Rc', Rc", Rd, Rd' and Rd" are each independently selected from hydrogen, alkyl, cycloalkyl, hydroxyalkyl, alkoxyalkyl, aryloxyalkyl, alkenyl, alkynyl, aryl, acyl, heterocycloalkyl, sulfonyl, alkylsulfonyl, arylsulfonyl, aminosulfonyl, nitroalkyl, aminoalkyl, monoalkylaminoalkyl,
10 di alkyl aminoalkyl, carboxy, amino, nitro, cyano, acyl, aminocarbonyl, hydroxy,
alkoxy, aryloxy, aminocarbonyloxy, carbonylamino, sulfonylamino or aralkyl, any of which is optionally substituted.
When a group is optionally substituted, the optional substituents can be one or more non-hydrogen substituents, provided that the resulting compound is
15 stable. Values of optional substituents are halogen, hydroxy, alkyl, cycloalkyl,
aralkyl, aryl, thiol, amino, mono alkyl amino, dialkylamino, formylamino, aminoiminomethyl, acylamino, aminoacyl, mono- or di- alkylaminocarbonyl, thiocarbonylamino, thioacylamino, aminothiocarbonyl, alkoxy, aryloxy, aminocarbonyloxy, mono- or di-alkylaminocarbonyloxy, mono- or
20 diarylaminocarbonyloxy, mono- or diaralkylaminocarbonyloxy, alkylsulfonyl,
arylsulfonyl, aralkylsulfonyl, alkylsulfonylamino, arylsulfonylamino, aralkylsulfonylamino, alkoxycarbonylamino, aralkoxycarbonylamino,

WO 01/46193 PCT/US00/34911
aryloxycarbonylamino, mono- or di- alkylaminothiocarbonyl, aralkoxy, carboxy, carboxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, nitro, cyano, trifluoromethyl, alkylthio and arylthio.
Preferred values of optional substituents on alkyl and cycloalkyl groups
5 are chloro, hydroxy, amino, mono(C1-4)alkylamino, di(C1-4)alkylamino,
formylamino, C2-6 acylamino, aminocarbonyl, C2_8 aminoacyl, C1-6 alkoxy, C6-14 aryloxy, carboxy, carboxy(C1-6)alkyl, C2-8 alkoxycarbonyl, nitro, cyano, trifluoromethyl, C1-6 alkylthio, C6-I4 arylthio, C,1-6 alkylsulfonylamino, C7-15 aralkylsulfonylamino, C6-.10 arylsulfonylamino, mono- or di(C1_
10 6)alkylaminocarbonyloxy, mono- or di- (C6_l0)arylaminocarbonyloxy, mono- or
di(C7.i5)aralkylcarbonyloxy, C1-6 alkoxycarbonylamino, C7-C15 aralkoxycarbonylamino, and C6-C10 aryloxycarbonylamino.
Preferred values of optional substituents on aryl-containing and heterocyclic-containing groups include chloro, hydroxy, amino, mono(C1-4)
15 alkylamino, di(C1-4)alkylamino, formylamino, C2-6 acylamino, aminocarbonyl, C2-8
aminoacyl, C3.7 cycloalkyl, C1-6 alkyl, Cl-6 alkoxy, C6-14 aryloxy, carboxy, carboxy(C1-6)alkyl, C2_8 alkoxycarbonyl, nitro, cyano, trifluoromethyl, C1-6 alkylthio, C6_14 arylthio, C6-l4 aryl, phenyl (further optionally substituted by one, two or three of chloro, hydroxy, C1-4 alkyl, C1-4 alkoxy, amino or carboxy),
20 tetrazolyl (further optionally substituted by one, two or three of chloro, hydroxy,
C1-4 alkyl, C1-4 alkoxy, amino or carboxy), thienyl (further optionally substituted by one, two or three of chloro, hydroxy, C1-4 alkyl, C14 alkoxy, amino or carboxy), 3,4-methylenedioxy, 3,4-ethylenedioxy, 3,4-propylenedioxy, C,^ alkylsulfonylamino, C7-15 aralkylsulfonylamino, C1-6 arylsulfonylamino, C1-6
25 alkylsulfonyl, C 6-10 arylsulfonyl, mono- or di(C1-6)alkylaminocarbonyloxy, mono-
or di- C6-10 arylaminocarbonyloxy, mono- or di-(C7-15 ) aralkylcarbonyloxy, C1-6 alkoxycarbonylamino, C7-C15 aralkoxycarbonylamino, C6-C10 aryloxycarbonylamino, C2-6 thioacylamino, aminothiocarbonyl, and C2-.8 aminothioacyl.
30 Preferred values of R1, R2 and R3 are hydrogen.

WO 01/46193 PCT/US00/34911
-6-
Preferred values of Rb, Rb', Rb", Rc, Rc' and Rc" are hydrogen, C1_6 alkyl, C3-8 cycloalkyl, sulfonyl, and C6.-14 aryl, any of which is optionally substituted.
Preferred values of Ra, Ra', Ra", Rd, Rd' and Rd" are hydrogen, C1-6 alkyl,
sulfonyl and C6-14 ar(C1-6)alkyl, any of which is optionally substituted.
5 Methods for the preparation of various 3-, 4-, 5- and 6-substituted
naphthyridines as starting materials for the preparation of the correspondingly
substituted triazatrinaphthyrins are described herein. Functional group
manipulation of the 3-, 4-, 5- and 6-positions (Ra, Ra', Ra", Rb, Rb", Rb" Rc, Rc', Rc"
Rd, Rd' and Rd") is possible after macrocycle formation, or the appropriately
10 substituted naphthyridines may be used directly, depending upon the particular
triazatrinaphthyrin desired.
Triazatrinaphthyrin itself (wherein R'-R3 and Ra, Ra', Ra" Rb, Rb, Rb", Rc,
Rc', Rc" Rd, Rd' and Rd" are each hydrogen) is a macrocycle which is generally
characterized by the presence of three 2-amino-l,8-naphthyridine subunits
15 contained within a macrocyclic framework and by emission bands that are red
shifted as compared to those of porphyrins.
Triazatrinaphthyrin and its substituted derivatives are characterized by the ability to form complexes with metal ions.
Triazatrinaphthyrin and its substituted derivatives are further
20 characterized by the ability to undergo facile protonation at one or more
naphthyridine nitrogens and/or bridging "meso" nitrogens. It is understood that
the triazatrinaphthyrin compounds of the present invention may be either singly
or doubly protonated, and in certain embodiments triply or four-fold protonated.
The term "alkyl" as employed herein by itself or as part of another group
25 refers to both straight and branched chain radicals of up to 12 carbons, such as
methyl, ethyl, propyl, isopropyl, butyl, t-butyl, isobutyl, pentyl, hexyl, isohexyl,
heptyl, 4,4-dimethylpentyl, octyl, 2,2,4-trimethylpentyl, nonyl, decyl, undecyl,
dodecyl.
The term "alkenyl" is used herein to mean a straight or branched chain
30 radical of 2-20 carbon atoms, wherein there is at least one double bond between
two of the carbon atoms in the chain including, but not limited to, ethenyl, 1-

WO 01/46193 PCT/US00/34911
-7-
propenyl, 2-propenyl, 2-methyl-l-propenyl, 1-butenyl, 2-butenyl, and the like.
Preferably, the alkenyl chain is 2 to 10 carbon atoms in length, more preferably,
2 to 8 carbon atoms in length most preferably from 2 to 4 carbon atoms in length.
The term "alkynyl" is used herein to mean a straight or branched chain
5 radical of 2-20 carbon atoms, wherein there is at least one triple bond between
two of the carbon atoms in the chain, including, but not limited to, acetylene,
1-propylene, 2-propylene, and the like. Preferably, the alkynyl chain is 2 to 10
carbon atoms in length, more preferably, 2 to 8 carbon atoms in length, most
preferably from 2 to 4 carbon atoms in length.
10 In all instances herein where there is an alkenyl or alkynyl moiety as a
substituent group, the unsaturated linkage, i.e., the vinylene or acetylene linkage
is preferably not directly attached to a nitrogen, oxygen or sulfur moiety.
The term "alkylthio" as employed herein by itself or as part of another
group refers to a straight or branched chain radical of 1 to 20 carbon atoms,
15 bonded to a sulfur atom, including, but not limited to, methylthio, ethylthio, n-
propylthio, isopropylthio, and the like. Preferably the alkylthio chain is 1 to 10
carbon atoms in length, more preferably 1 to 8 carbon atoms in length.
The term "alkoxy" as employed herein by itself or as part of another group
refers to a straight or branched chain radical of 1 to 20 carbon atoms, bonded to
20 an oxygen atom, including, but not limited to, methoxy, ethoxy, rc-propoxy,
isopropoxy, and the like. Preferably the alkoxy chain is 1 to 10 carbon atoms in
length, more preferably 1 to 8 carbon atoms in length.
The term "cycloalkyl" as employed herein by itself or as part of another
group refers to cycloalkyl groups containing 3 to 9 carbon atoms. Typical
25 examples are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,
cyclooctyl and cyclononyl.
The term "halogen" or "halo"as employed herein by itself or as part of
another group refers to chlorine, bromine, fluorine or iodine with chlorine being
preferred.
30 The term "acyl" as employed herein by itself or as part of another group
refers to the group -C(O)Rg where Rg is alkyl, alkenyl, alkynyl, aryl, aralkyl,

WO 01/46193 PCT/US00/34911
aralkenyl, heteroaryl, heteroarylalkyl or heteroarylalkenyl. Preferred acyl groups are alkanoyl, aralkanoyl and aroyl groups (-C(O)Rg where R8 is C,.B alky], C6.10 aryI(C1-.4)alkyl or C6.l0 aryl).
The term "thioacyl" as employed herein by itself or as part of another
5 group refers to the group -C(S)Rg where R8 is alkyl, alkenyl, alkynyl, aryl, aralkyl,
aralkenyl, heteroaryl, heteroarylalkyl or heteroarylalkenyl, preferably C,_8 alkyl.
The term "thiocarbonyl" as employed herein by itself or as part of another group refers to the group -C(S)-.
The term "monoalkylamine" as employed herein by itself or as part of
10 another group refers to an amino group which is substituted with one alkyl group
having from 1 to 6 carbon atoms.
The term "dialkylamine" as employed herein by itself or as part of another group refers to an amino group which is substituted with two alkyl groups, each having from 1 to 6 carbon atoms
15 The term "aryl" as employed herein by itself or as part of another group
refers to monocyclic or bicyclic aromatic groups containing from 6 to 14 carbons in the ring portion, preferably 6-10 carbons in the ring portion, such as phenyl, naphthyl or tetrahydronaphthyl.
The term "aralkyl" or "arylalkyl" as employed herein by itself or as part
20 of another group refers to C1_6alkyl groups as discussed above having an aryl
substituent, such as benzyl, phenylethyl or 2-naphthylmethyl.
The terms "heterocyclic," "heterocyclo" or "heterocycle" as employed
herein by themselves or as part of larger groups refers to a saturated or wholly or
partially unsaturated 3-7 membered monocyclic, or 7-10 membered bicyclic ring
25 system, which consists of carbon atoms and from one to four heteroatoms
independently selected from the group consisting of O, N, and S, wherein the
nitrogen and sulfur heteroatoms can be optionally oxidized, the nitrogen can be
optionally quaternized, and including any bicyclic group in which any of the
above-defined heterocyclic rings is fused to a benzene ring, and wherein the
30 heterocyclic ring can be substituted on carbon or on a nitrogen atom if the
resulting compound is stable. Especially useful are rings containing one oxygen

WO 01/46193 PCT/US00/34911
or sulfur, one to three nitrogen atoms, or one oxygen or sulfur combined with one
or two nitrogen atoms. Examples of such heterocyclic groups include piperidinyl,
piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolodinyl, 2-
oxoazepinyl, azepinyl, pyrrolyl, 4-piperidonyl, pyrrolidinyl, pyrazolyl,
5 pyrazolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, pyridyl, pyrazinyl,
pyrimidinyl, pyridazinyl, oxazolyl, oxazolidinyl, isoxazolyl, isoxazolidinyl, morpholinyl, thiazolyl, thiazolidinyl, isothiazolyl, quinuclidinyl, isothiazolidinyl, indolyl, indanyl, quinolinyl, isoquinolinyl, benzimidazolyl, thiadiazoyl, benzopyranyl, benzothiazolyl, benzoxazolyl, furyl, tetrahydrofuryl,
10 tetrahydropyranyl, thienyl, benzothienyl, thiamorpholinyl, thiamorpholinyl
sulfoxide, thiamorpholinyl sulfone, and oxadiazolyl. Morpholino is the same as morpholinyl.
The term "heteroatom" is used herein to mean an oxygen atom ("O"), a sulfur atom ("S") or a nitrogen atom ("N"). It will be recognized that when the
15 heteroatom is nitrogen, it may form an NRyRz moiety, wherein Ry and Rz are,
independently from one another, hydrogen or C, to C8 alkyl, or together with the nitrogen to which they are bound, form a saturated or unsaturated 5-, 6-, or 7-membered ring.
The term "heteroaryl" as employed herein refers to groups having 5 to 14
20 ring atoms; 6,10 or 14 n electrons shared in a cyclic array; and containing carbon
atoms and 1, 2 or 3 oxygen, nitrogen or sulfur heteroatoms (where examples of heteroaryl groups are: thienyl, benzo[b] thienyl, naphtho[2,3-b]thienyl, thianthrenyl, furyl, pyranyl, isobenzofuranyl, benzoxazolyl, chromenyl, xanthenyl, phenoxathiinyl, 2ff-pyrrolyl, pyrrolyl, imidazolyl, pyrazolyl, pyridyl,
25 pyrazinyl, pyrimidinyl, pyridazinyl, indolizinyl, isoindolyl, 3//-indolyl, indolyl,
indazolyl, purinyl, 4tf-quinolizinyl, isoquinolyl, quinolyl, phthalazinyl, naphthyridinyl, quinazolinyl, cinnolinyl, pteridinyl, 4octf-carbazolyl, carbazolyl, p-carbolinyl, phenanthridinyl, acridinyl, perimidinyl, phenanthrolinyl, phenazinyl, isothiazolyl, phenothiazinyl, isoxazolyl, furazanyl and phenoxazinyl groups).
30 The term "substituted", as used herein, means that one or more hydrogens
of the designated moiety are replaced with a selection from the indicated group,

WO 01/46193 PCT/US00/34911
provided that no atom's normal valency is exceeded, and that the substitution results in a stable compound. When a substituent is keto (i.e., =O), then 2 hydrogens attached to an atom of the moiety are replaced.
By "stable compound" or "stable formula" is meant herein a compound
5 that is sufficiently robust to survive isolation to a useful degree of purity from a
reaction mixture and formulation into an efficacious therapeutic or diagnostic agent.
The triazatrinaphthyrin macrocycles of the present invention may be protonated and exist in the form of a salt. The terms "salt", "acid addition salt" or
10 "pharmaceutically acceptable salt" are intended to include all acceptable salts.
Examples of acid salts are hydrochloric, hydrobromic, hydrofluoric, perchloric, nitric, sulfuric, phosphoric, formic, acetic, trifluoroacetic, propionic, maleic, succinic, malonic, methane sulfonic and the like. A triazatrinaphthyrin macrocycle of the present invention in the form of a salt is characterized by the
15 pronation of one of more nitrogen atoms. The complete salt consists of the
monoprotonated or multiprotonated macrocycle and its associated anion(s).
Macrocycle Synthesis
The preferred starting material for the preparation of the triazatrinaphthyrin macrocycles of the present invention is the appropriately
20 substituted 2,7-diamino-1,8-naphthyridine.
Scheme 1 illustrates the synthetic sequence for the preparation of various 2,7-diamino-1,8-naphthyridines (5a). As shown, this is accomplished by reacting the corresponding 2-amino-7-chloro-l,8-naphthyridine (4) or 2,7-dichloro-l,8-naphthyridine (7) with anhydrous ammonia or other amine. The 2-amino-7-
25 chloro-l,8-naphthyridines (4) can be prepared according to the method of
Carboni, S. etal, Gazz. Chim. hah 96(11): 1456-1459 (1966), herein incorporated by reference in its entirety, which begins with the formation of 2-amino-7-hydroxy-l,8-naphthyridine (3) from the appropriately substituted 2,6-diaminopyridine (1) and p-ketoester (2). Those of skill in the art of organic

WO 01/46193 PCT/US00/34911
synthesis will appreciate the availability of alternate reagents and conditions for affecting the conversions outlined in Scheme 1.

5 2,7-diamino-l,8-naphthyridines ((5), R1" = RIV=H) maybe functionalized
to provide the desired Ra, Ra', Ra", Rb, Rb', Rb", Rc, Rc', Rc", Rd, Rd' and Rd" groups
of Formula /. For example, as shown in Scheme 2 below, protection of the 2- and
7-amino groups with a suitable protecting group and subsequent treatment with
base generates one or more nucleophilic carbon atoms on the naphthyridine ring
10 which can react with the appropriate electrophile (e.g., alkyl halides, epoxides,
anhydrides, sulfonate esters and the like) to arrive at a functionalized 2,7-diaminonaphthyridine for use in the subsequent macrocycle forming reaction.

WO 01/46193 PCI
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For certain Ra, Ra', Ra", Rb, Rb', Rb", Rc, Rc', Rc", Rd, Rd' andRd" substituents
of Formula I which are incompatible with the reaction conditions of macrocycle
5 formation, and which cannot be prepared by derivatization of other groups,
functional group manipulation of those positions may be carried out after
macrocycle formation.
The synthetic strategies outlined herein allow for the formation of triazatrinaphthyrins wherein Ra, Ra', Ra", Rd, Rd' and Rd" of Formula / are
10 hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl, aryloxyalkyl, alkenyl, alkynyl, acyl,
heterocycloalkyl, alkylsulfonyl, arylsulfonyl, nitroalkyl, aminoalkyl, monoalkylaminoalkyl, dialkylaminoalkyl or aralkyl, any of which is optionally substituted; and Rb Rb', Rb", Rc, Rc', and Rc" of Formula / are each independently selected from hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, aralkyl, carboxy,
15 amino, nitro, cyano, acyl, aminocarbonyl, alkylsulfonyl, arylsulfonyl,
aminosulfonyl, hydroxy, alkoxy, aryloxy, aminocarbonyloxy, carbonylamino, sulfonylamino, any of which is optionally substituted.

WO 01/46193 PCT/US00/34911
Scheme 3 illustrates the synthesis of the parent triazatrinaphthyrin
(wherein Ra, Ra,' Ra", Rb, Rb', Rb", Rc, Rc', Rc", Rd, Rd' and Rd" of Formula/ are each
hydrogen). The macrocycle forming reaction is carried out in a vertical
Abderhalden apparatus (see Figure 1) or in a tube furnace, the latter providing
5 better temperature control. In general, the macrocycle forming reaction is
characterized by the treatment of a 2,7-diamino-1,8-naphthyridine with hydrogen halide gas at a temperature sufficient to cause melting of the 2,7-diamino-l,8-naphthyridine in 1 atmosphere of hydrogen halide gas. While not intending to be limited to any mechanistic explanation, the reaction is believed to proceed by
10 elevation ofahydrohalidesalt of2,7-diamino-l,8-naphthyridine to a temperature
sufficient to cause amine extrusion and triazatrinaphthyrin formation. The details of an embodiment of the synthesis as carried out in the Abderhalden apparatus are outline in Example 1.
It is to be understood that the macrocycle-forming reaction can be carried
15 out with a single 2,7-diamino- 1,8-naphthyridine or with a mixture of 2,7-
diamino- 1,8-naphthyridines. When the macrocycle-forming reaction is carried out with a mixture of 2,7-diamino-1,8-naphthyridines, a mixture of products (including various regioisomers) is obtained. One of skill in the art will appreciate various chromatographic media and solvent systems capable of
20 separating a mixture of triazatrinaphthyrins and isolating the desired compound
from the mixture. Typical chromatographic media include various mesh sizes of silica gel or alumina and typical solvent systems include mixtures of polar and non-polar solvents such as CHC13/CH3OH, CH2C12/CH3OH, and others known in the art of chrornatography.
25 An alternative embodiment of the process for forming triazatrinaphthyrins
involves the use of a hydrohalide salt of an aromatic amine or a mixture of aromatic amines (including, but not limited to, pyridinium hydrochloride, quinoline hydrochloride or 4-(3-phenylpropyl)pyridine hydrochloride) as a solvent in which a 2,7-diamino-l,8-naphthyridine is dissolved and the
30 temperature elevated sufficiently to cause melting of the solvent and amine

WO 01/46193 PCT/US00/34911
-14-
extrusion and triazatrinaphthyrin formation. Certain solvents, such as pyridinium hydrochloride, when heated to near its boiling point of 222 °C, facilitate the formation of triazatrinapthyrin in 1 atmosphere of hydrogen chloride at temperatures well below 300 °C.
5 At sufficiently elevated temperatures, the use of hydrogen chloride or a
hydrohalide salt may not be necessary to effect formation of the
triazatrinapthyrin. Specifically, the di-n-propyl-diaminonaphthyriine outlined in
Scheme 2, when heated rapidly and briefly to its melting point of about 340 °C
in a sealed tube, spontaneously forms the corresponding hexapropyl
10 triazatrinapthyrin in good yield. Accordingly, the present invention also
encompasses a process for forming a triazatrinaphthyrin by heating a 2,7-diamino-l,8-naphthyridine at, or above, its melting temperature to yield the desired triazatrinaphthyrin.

WO 01/46193 PCT/US00/34911
Metalation/Addition of Radioisotopes
The triazatrinaphthyrin compounds of the present invention include those
where the triazatrinaphthyrin is complexed with certain metals for use as a
transition metal complexing agent, or simply as a convenient form of the
5 compound. Examples of metals which are appropriate include paramagnetic ions
of elements such as Gd, In, Eu, Dy, Pr, Pa, Cr, Co, Fe, Cu, Ni, Ti, and V,
preferably Gd or Eu. Complex formation is typically carried out in a polar
solvent, including but not limited to, water, isopropanol, ethanol, methanol,
acetone, DMF, DMSO, acetonitrile and the like. Solvent systems including a
10 mixture of solvents and/or aqueous solvent mixtures are also contemplated.
Typically, the metal ion in the form of its halide or acetate salt is used in the complex forming reaction. An exemplary complex forming reaction is described in Example 2.
Protonated Macrocycles
15 Triazatrinaphthyrins undergo facile protonation at one or more
naphthyridine nitrogens or at one or more apical (or "meso") nitrogens. Typically, a triazatrinaphthyrin is contacted with an acid selected from hydrochloric, hydrobromic, hydrofluoric, perchloric, nitric, sulfuric, phosphoric, formic, acetic, trifluoroacetic, propionic, maleic, succinic, malonic, and methane
20 sulfonic in an aqueous solution. The resulting singly or multi-protonated
macrocycle is associated with one or more negatively charged counterions, depending on the acid used to protonate the macrocycle.
Example 1
11,22,33- Triazatrinaphthyrin
25 a. 2,7-Diamino-l,8-naphthyridine. 2-Amino-7-chloro-l,8-
naphthyridine (50 grams, 0.28 moles), prepared by the method of Carboni, S. et al, Gazz. Chim. Ital. 96(11): 1456-1459 (1966), was loaded into a 2 liter Parr

WO 01/46193 PCT/US00/34911
-16-
bomb and charged with liquid anhydrous ammonia (500 ml). The bomb was
sealed, brought to a pressure of 1200 PSI, and maintained at this pressure for 14
hours. The bomb was thencooled to room temperature, the ammonia vented, and
the bomb contents extracted, first with 1.5 liters of saturated aqueous ammonia,
5 then with 500 ml of saturated aqueous ammonia. These clear yellow liquid
extracts were combined and concentrated on the rotary evaporator to a volume of about 250 ml, yielding a flocculent precipitate which was collected and dried to give the product 2,7-diamino-l,8-naphthyridine (26 g, 162 mmol, 58%), mp 311°C (lit. mp = 222-223 °C; Collin, J.-P., et ai, Inorg Chim. Acta 201:29-34
10 (1992)). lHNMR(DMSO-d6):67.76(d,7=9Hz,2H,C//),71.4(br.s.)4H,NH2),
6.50(d,J=9Hz,CH). l3CNMR: 6 160.7,144.4,140.2,109.9,108.6. MS m/e 160 (100%), 133 (25%), 105 (9%). HRMS calc'd for C8H8N4: m/e= 160.074896. Found: m/e= 160.074984. UV-visible 2max (log e) (25% aqueous EtOH): 352(4.07). Emission 2max (arbitrary units) (25% aq.. EtOH/IPA):, 407(0.48),
15 493(1.00).
b. 11,22,33-Triazatrinaphthyrin. A custom-built vertical Aberhalden apparatus (see Figure 1) was charged with 2,7-diamino-l,8-naphthyridine (12 grams) and capped with a stoppered top leading to a manifold capable of replacing a vacuum with 1 atmosphere of anhydrous hydrogen chloride gas. The
20 diaminonaphthyridine was held under vacuum in the inner chamber of the
Aberhalden vessel until such time as condensing vapors of sulfuric acid (bp=300 °C) began to bathe the outside of the inner chamber and the diaminonaphthyridine began to change color from the heat. The vacuum was then promptly replaced with 1 atm of anhydrous hydrogen chloride. The
25 diaminonaphthyridine quickly melted, darkened, and began to bubble. After 40
minutes the darkened reaction mass had completely resolidified, and heating was continued for an additional 20 minutes. The apparatus was allowed to cool, and the crude product was removed from the vessel and ground to a powder. This whole process was repeated and the two batches were combined and washed as
30 follows: The dark powder was stirred with 200 ml concentrated aqueous

WO 01/46193 PCT/US00/34911
ammonia for 30 minutes, then filtered, and the moist solid so obtained was
washed two more times by stirring for 1 hour with 500 ml warm ethanol saturated
with ammonia vapor. The remaining solid material (dry weight 19 grams) was
stirred for 12 hours in 250 ml of glacial acetic acid held at 60 °C. The resultant
5 dark solution was filtered through a medium glass fritted funnel and concentrated
to dryness on a rotary evaporator. The residue so obtained was dried in vacuo at
100 °C for 24 h to give the product as a dark purple solid (16.5 g, 38.5 mmole,
77%). 'H NMR (CF3COOD): 6 7.98 (d, J=9.3 Hz, 2H, CH), 6.95 (d, J=93 Hz,
CH). 13CNMR(CF3COOD): 6 155.5, 144.8, 144.3, 118.1, 116.3. MS m/e 429
10 (100%), 214 (10%). HRMS calc'd for C24H9: m/e= 429.1450. Found:
m/e=429.1449. UV-visible 2max (log e) (HOAc): 340 (4.78), 356 (4.96), 406 (3.51), 480-82sh (3.11). Emission 2max (arbitrary units)(sh = shoulder) (concentrated HC1): 535-542sh (0.275), 569 (1.00), 615 (0.29).
Example 2
15 11,22,33~Triazatrinaphthyrin o Gd(III) Acetate
A 50 mL flask is charged with 11,22,33-triazatrinaphthyrin (100 mg, 0.23
mol) and 15 mL 33% aqueous acetic acid. The clear dark solution is stirred at
room temperature and Gd(III) chloride hexahydrate (75 mg, 0.20 mol) in 2 mL
of water is added in one portion. Complex formation may monitored by
20 observing the characteristic changes in UV-Vis absorption, although complex
formation is essentially complete within a minute. The resulting solution is evaporated under reduced pressure and washed with glacial acetic acid to remove uncomplexed triazatrinaphthyrin. The resulting complex is obtained in quantitative yield based on the amount of staring Gd(EH) chloride hexahydrate.
25 Extraction of Metals
Besides the nine elements of Group VIII of the periodic table, the transition metals include the elements of Groups 3A to 7A and Groups 1B and 2B, that is, the elements ranging from scandium, having an atomic number of 21,

WO 01/46193 PCT/US00/34911
-18-
to zinc, having an atomic number of 30, from yttrium, having an atomic number
of 39, to cadmium, having an atomic number of 48, from lanthanum, having an
atomic number of 57, to mercury, having an atomic number of 80, and from
actinium, having an atomic number of 89, to lawrencium, having an atomic
5 number of 103. Specifically, the transition metals include the elements of Group
VIII, i.e., iron (Fe), cobalt (Co), nickel (Ni), ruthenium (Ru), rhodium (Rh), palladium (Pd), osmium (Os), iridium (IT), and platinum (Pt), and further include titanium (Ti), vanadium (V), chromium (Cr), manganese (Mn), copper (Cu), zinc (Zn), yttrium (Y), zirconium (Zr), niobium (Nb), molybdenum (Mo), silver (Ag),
10 cadmium (Cd), lanthanum (La), cerium (Ce), neodymium (Nd), samarium (Sm),
europium (Eu), gadolinium (Gd), terbium (Tb), holmium (Ho), erbium (Er), thulium (Tin), ytterbium (Yb), lutetium (Lu), hafnium (Hf), tantalum (Ta), tungsten (W), gold (Au), mercury (Hg), uranium (U), and plutonium (Pu).
The solution to be extracted is not particularly limited in the concentration
15 of transition metals dissolved therein. Even when the solution has a transition
metal concentration as low as about 1.0 x 10"5 M, it is expected to be sufficiently extracted.
Although the aqueous transition metal solution is not particularly limited in pH, it preferably has a pH below 6. As the pH of the solution is altered, the
20 degree of extraction may tend to decrease. In this case, a longer extraction period
is necessary as is know in the art
The extraction temperature is not particularly limited as long as it is not higher than the boiling point of the solvent used. In general, a temperature around room temperature may be used.
25 The extraction operation is conducted by bringing a solution of the
triazatrinaphthyrin into contact with a solution containing transition metals dissolved therein. This contacting is accomplished by shaking, stirring, etc. Although conditions for shaking or stirring are not particularly limited, vigorous shaking or agitation is more effective in efficient extraction. Shaking may be
30 usually conducted at a frequency of about from 100 to 400 times per minute.

WO 01/46193 PCT/US00/34911
An additive for accelerating the extraction (extraction accelerator) can also be used.
Examples of the extraction accelerator include basic nitrogen-containing
heterocyclic compounds and aromatic amino acids. Specific examples thereof
5 include nitrogen-containing heterocyclic compounds, such as pyridine,
alkylpyridinas (e.g., methylpyridine, ethylpyridine), and quinoline; and amino
acids containing an aromatic ring, such an tryptophan and phenylalanine.
Examples of the extraction accelerator further include compounds which
coordinate to transition metal ions and help the ions to associate with the
10 triazatrinaphthyrin and which thus function to heighten the rate of complex
formation with transition metal ions. However, pyridine and tryptophan are
preferred.
Although the concentration of the extraction accelerator is not particularly
limited, the amount thereof is preferably from 1 to 1,000 gram equivalents per
15 gram equivalent of the transition metal ions to be extracted.
If the amount of the extraction accelerator is too small, the effect of accelerating extraction is not obtained. Conversely, if the amount thereof is too large, there is a fear that the accelerator may alter the properties of the solvent used in an organic phase.
20 The composition for extracting a transition metal of the present invention
is useful for efficiently extracting transition metals, particularly lanthanides, such as gadolinium.
Extraction Example
Extraction of transition metals with a triazatrinaphthyrin of the present
25 invention may be carried out as follows:
In the extraction experiment, 10 ml of an organic phase is prepared by dissolving triazatrinaphthyrin acetate (or other triazatrinaphtyrin macrocycle, salt or complex) in chloroform in a concentration of 5.0 x 10-4 M and placing the same in a 30-ml screw vial together with 10 ml of an acetic acid phase containing

WO 01/46193 PCT/US00/34911
-20-
transition metal chlorides in an amount of 1.0 x 10-4 M, and the contents are
shaken for 24 hours. In determining the degree of extraction for each metal, the
acetic acid phase after the shaking is analyzed with an atomic absorption
photometer to determine the concentration of ions of the metal remaining therein.
5 The degree of extraction is calculated using the following equation, wherein
M+tolal means the initial concentration of the metal ions and M+solulion means the found metal ion concentration in the acetic acid phase after the extraction experiment.

10 Having now fully described this invention, it will be understood to those
of ordinary skill in the art that the same can be performed within a wide and equivalent range of conditions, formulations, and other parameters without affecting the scope of the invention or any embodiment thereof. All patents and publications cited herein are fully incorporated by reference herein in their
15 entirety.

WO 01/46193 PCT/US00/3491!
-21-
Whats Claimed Is:

or a solvate, hydrate, ester or salt thereof; wherein:
5 R1, R2 and R3 are each independently selected from hydrogen, alkyl,
cycloalkyl, aryl, aralkyl, heterocycle and formyl, any of which is optionally substituted;
Ra, Ra', Ra", Rb, Rb', Rb", Rc, Rc', Rc", Rd, Rd' and Rd" are each independently
selected from hydrogen, alkyl, cycloalkyl, hydroxyalkyl, alkoxyalkyl,
10 aryloxyalkyl, alkenyl, alkynyl, aryl, acyl, heterocycloalkyl, sulfonyl, alkylsulfonyl,
arylsulfonyl, aminosulfonyl, nitroalkyl, aminoalkyl, monoalkylaminoalkyl, dialkylaminoalkyl, carboxy, amino, nitro, cyano, acyl, aminocarbonyl, hydroxy, alkoxy, aryloxy, aminocarbonyloxy, carbonylamino, sulfonylamino or aralkyl, any of which is optionally substituted.
15 2. A compound of claim 1, wherein R1 , R2, R3, Ra, Ra', Ra", Rb, Rb',
Rb", Rc, Rc', Rc", Rd, Rd' and Rd" are each hydrogen.
3. A compound of claim 1, wherein said optional substituents are selected from halogen, hydroxy, alkyl, cycloalkyl, aralkyl, aryl, thiol, amino,

WO 01/46193 PCT/US00/34911
-22-
monoalkylamino, dialkylamino, formylamino, aminoiminomethyl, acylamino,
aminoacyl, mono- or di- alkylaminocarbonyl, thiocarbonylamino> thioacylamino,
aminothiocarbonyl, alkoxy, aryloxy, aminocarbonyloxy, mono- or di-
alkylaminocarbonyloxy, mono- or diarylaminocarbonyloxy, mono- or
5 diaralkylaminocarbonyloxy, alkylsulfonyl, arylsulfonyl, aralkylsulfonyl,
alkylsulfonylamino, arylsulfonylamino, aralkylsulfonyl am in o, alkoxycarbonylamino, aralkoxycarbonylamino .aryloxycarbonylamino, mono- or di- alkylaminothiocarbonyl, aralkoxy, carboxy, carboxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, nitro, cyano, trifluoromethyl, alkylthio and arylthio.
10 4. A compound of claim 1, in the form of a monoprotonated or
multiprotonated acid addition salt, wherein the acid is selected from the group consisting of hydrochloric, hydrobromic, hydrofluoric, perchloric, nitric, sulfuric, phosphoric, formic, acetic, trifluoroacetic, propionic, maleic, succinic, malonic, and methane sulfonic.
15 5. A salt comprising a singly-protonated or multi-protonated
compound of claim 1 and at least one negatively charged counterion.
6. A metal complex comprising a compound of claim 1 and a metal
ion.
7. A metal complex of claim 6, wherein said metal is selected from
20 the group consisting of Tc, In, Ga, Gd, Eu, Dy, Pr, Pa, Cr, Co, Fe, Cu, Ni, Ti, and
V.
8. A complex according to claim 6, wherein said metal is
paramagnetic.
9. A metal complex of claim 8, wherein said metal is Gd(DI) or
25 Eu(III).

WO 01/46193 PCT7US00/34911
10. A method of forming a compound of Formula /:

or a solvate, hydrate, ester or salt thereof; wherein:
R1, R2 and R3 are each independently selected from hydrogen, alkyl,
5 cycloalkyl, aryl, aralkyl, heterocycle and formyl, any of which is optionally
substituted;
Ra, Ra', Ra", Rb, Rb', Rb", Rc, Rc', Rc" Rd, Rd' and Rd" are each independently
selected from hydrogen, alkyl, cycloalkyl, hydroxyalkyl, alkoxyalkyl,
aryloxyalkyl, alkenyl, alkynyl, aryl, acyl, heterocycloalkyl, sulfonyl, alkylsulfonyl,
10 arylsulfonyl, aminosulfonyl, nitroalkyl, aminoalkyl, monoalkylaminoalkyl,
dialkylaminoalkyl, carboxy, amino, nitro, cyano, acyl, aminocarbonyl, hydroxy, alkoxy, aryloxy, aminocarbonyloxy, carbonylamino, sulfonylamino or aralkyl, any of which is optionally substituted, comprising:
(a) treating a compound of Formula//
15
wherein Ra, Rb, Rc and Rd are as defined above, with hydrogen chloride gas.

WO 01/46193 PCT/US00/34911
-24-
11. A method for extracting a transition metal, such as herein described, which comprise contacting a material containing the transition metal with a composition which comprises as an active extracting ingredient a compound of the following Formula:
5
or a solvate, hydrate, ester or salt thereof; wherein:
R], R2 and R3 are each independently selected from hydrogen, alkyl, cycloalkyl, aryl, aralkyl, heterocycle and formyl, any of which is optionally substituted;
10 Ra, Ra' R'", R, Rb', Rb" Rc, Rc', Rc" Rd, Rd" and Rd" are each independently
selected from hydrogen, alkyl, cycloalkyl, - hydroxyalkyl, alkoxyalkyl, aryloxyalkyl, alkenyl, alkynyl, aryl, acyl, heterocycloalkyl, sulfonyl, alkylsulfonyl, arylsulfonyl, aminosulfonyl, nitroalkyl, aminoalkyl, monoalkylaminoalkyl, dialkylaminoalkyl, carboxy, amino, nitro, cyano, acyl, aminocarbonyl, hydroxy,
15 alkoxy, aryloxy, aminocarbonyloxy, carbonylamino, sulfonylammo or aralkyl,
any of which is optionally substituted, to extract the transition metal from the material.
12. A composition for extracting a transition metal which comprises as an active ingredient a compound of the following Formula:

WO 01/46193 PCT/US00/34911
-25-

or a solvate, hydrate, ester or salt thereof; wherein:
R1 R2 and R3 are each independently selected from hydrogen, alkyl,
cycloalkyl, aryl, aralkyl, heterocycle and fomyl, any of which is optionally
5 substituted;
Ra, Ra', Ra", Rb, Rb', Rb", Rc, Rc', Rc", Rd, Rd' and Rd" are each independently
selected from hydrogen, alkyl, cycloalkyl, hydroxyalkyl, alkoxyalkyl,
aryloxyalkyl, alkenyl, alkynyl, aryl, acyl, heterocycloalkyl, sulfonyl, alkylsulfonyl,
arylsulfonyl, aminosulfonyl, nitroalkyl, aminoalkyl, monoalkylaminoalkyl,
10 dialkylaminoalkyl, carboxy, amino, nitro, cyano, acyl, aminocarbonyl, hydroxy,
alkoxy, aryloxy, aminocarbonyloxy, carbonylamino, sulfonylamino or aralkyl, any of which is optionally substituted, and an extraction accelerator selected from the group consisting of basic nitrogen-containing heterocyclic compounds and aromatic amino acids. The amount of extraction accelerator is preferably from 1 to 1,000 gram equivalents per gram equivalent of the transition metal ions to be extracted.
A novel class of macro-cycles, termed triazatrinaphtbyrins, is disclosed having general Formula (I) or a solvate, hydrate, ester or salt thereof; wherein R1, R2, R3, Ra, Ra' ,Ra", Rh, Rh' Rh", Rc, Rc', Rc", Rd, Rd" and Rd" are defined in the specification. The macrocycles are useful in the extraction of transition metals, in particular in the extraction of lanthanides.

Documents:

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in-pct-2002-00862-kol claims.pdf

in-pct-2002-00862-kol correspondence.pdf

in-pct-2002-00862-kol description(complete).pdf

in-pct-2002-00862-kol drawings.pdf

in-pct-2002-00862-kol form-1.pdf

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in-pct-2002-00862-kol letters patent.pdf

in-pct-2002-00862-kol reply f.e.r.pdf

IN-PCT-2002-00862-KOL-CORRESPONDENCE 1.1.pdf

IN-PCT-2002-00862-KOL-CORRESPONDENCE-1.2.pdf

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Patent Number

201757

Indian Patent Application Number

IN/PCT/2002/00862/KOL

PG Journal Number

11/2007

Publication Date

16-Mar-2007

Grant Date

16-Mar-2007

Date of Filing

26-Jun-2002

Name of Patentee

TRINAPCO INC

Applicant Address

SUIT 268, 1933 DAVIS STREET,SAN LEANDRO,CA 94577-1258,

Inventors:

#	Inventor's Name	Inventor's Address
1	JOHNSON MARTIN R	APT 22G, 1200 LAKESHORE DRIVE, OAKLAND CA 94606,

PCT International Classification Number

C07D 471/16

PCT International Application Number

PCT/US00/34911

PCT International Filing date

2000-12-22

PCT Conventions:

#	PCT Application Number	Date of Convention	Priority Country
1	60/171,583	1999-12-23	U.S.A.