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• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
  • A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
  • A61K51/04—Organic compounds
  • A61K51/0474—Organic compounds complexes or complex-forming compounds, i.e. wherein a radioactive metal (e.g. 111In3+) is complexed or chelated by, e.g. a N2S2, N3S, NS3, N4 chelating group
  • A61K51/0476—Organic compounds complexes or complex-forming compounds, i.e. wherein a radioactive metal (e.g. 111In3+) is complexed or chelated by, e.g. a N2S2, N3S, NS3, N4 chelating group complexes from monodendate ligands, e.g. sestamibi
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
  • A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
  • A61K51/04—Organic compounds
  • A61K51/0474—Organic compounds complexes or complex-forming compounds, i.e. wherein a radioactive metal (e.g. 111In3+) is complexed or chelated by, e.g. a N2S2, N3S, NS3, N4 chelating group
  • A61K51/0478—Organic compounds complexes or complex-forming compounds, i.e. wherein a radioactive metal (e.g. 111In3+) is complexed or chelated by, e.g. a N2S2, N3S, NS3, N4 chelating group complexes from non-cyclic ligands, e.g. EDTA, MAG3
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
  • C07B59/00—Introduction of isotopes of elements into organic compounds ; Labelled organic compounds per se
  • C07B59/004—Acyclic, carbocyclic or heterocyclic compounds containing elements other than carbon, hydrogen, halogen, oxygen, nitrogen, sulfur, selenium or tellurium
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
  • C07C229/02—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton
  • C07C229/04—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
  • C07C229/06—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one amino and one carboxyl group bound to the carbon skeleton
  • C07C229/10—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one amino and one carboxyl group bound to the carbon skeleton the nitrogen atom of the amino group being further bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings
  • C07C229/16—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one amino and one carboxyl group bound to the carbon skeleton the nitrogen atom of the amino group being further bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings to carbon atoms of hydrocarbon radicals substituted by amino or carboxyl groups, e.g. ethylenediamine-tetra-acetic acid, iminodiacetic acids
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C233/00—Carboxylic acid amides
  • C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
  • C07C233/34—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by amino groups
  • C07C233/42—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by amino groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by a carbon atom of a six-membered aromatic ring
  • C07C233/43—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by amino groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by a carbon atom of a six-membered aromatic ring having the carbon atom of the carboxamide group bound to a hydrogen atom or to a carbon atom of a saturated carbon skeleton
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K2123/00—Preparations for testing in vivo

Definitions

• This invention concerns compositions, and a method of treating and/or diagnosing soft tissue tumors in mammals with metal-phenolic carboxylate ligand complexes and their formulations.
• Gd-DTPA gadolinium-diethylenetriaminepentaacetic acid
• 99m Tc a pure gamma emitter, in the form of a metal ligand complex is routinely used as a diagnostic agent.
• 99m Tc-DTPA injection of the complex into the bloodstream does not result in the radionuclide localizing in any tissue. Instead, the radionuclide is eliminated from the body by the kidneys into the urine. In other cases, the radionuclide does localize in desired specific organs or tissues.
• specific 99m Tc-phosphonic acid complexes localize in bone [Radiology 149, 823-828 (1983)] and one of the uses of 99m Tc-phosphonic acid complexes is the detection of calcific tumors.
• Bifunctional chelating agents were developed to bind the metal ions to the monoclonal antibody through a chelating agent (the metal-ligand-antibody moiety is termed a "conjugate") and many such conjugates have emerged.
• conjugates use gamma emitters such as 99m Tc or 111 In for imaging (see for example U.S.
• Patents 4,454,106, 3,994,966, 4,662,420 and 4,479,930 propose a conjugate with particle emmiters such as 67 Cu [see for example J. C. Roberts et al., Appl. Rad. Isotopes 40(9), 775 (1989)] or 90 Y [see for example J. Nucl. Med. 26(5), 503 (1985)] for therapy. It was
• Another approach to delivering metals to soft tissue tumors is by means of a metal ligand complex.
• 67 Ga-citrate is presently used for detecting abscesses more than for tumor diagnosis, many clinicians prefer to use it over the monoclonal antibody conjugates for diagnosis. Even though 67 Ga-citrate is widely used, it has various disadvantages. For example, the rate of blood clearance is slow so that images are taken as much as 48 hours post injection with 67 Ga-citrate [see Int. J. Appl. Nucl. Med. Biol. 8, 249-255 (1984)]. In addition, high uptake of the 67 Ga-citrate in non-target tissues make images difficult to interpret [see Curr. Concepts in Diagn. Nucl. Med.1(4), 3-12 (1984)].
• EDTA ethylenediaminetetraacetie acid
• HEDTA hydroxyethylethylenediaminetriacetic acid
• chelates used a 20 to 1 HEDTA to Sm molar ratio and found tumor uptake to be significantly less than that of 67 Ga-citrate. An unacceptably large liver uptake was noted when using 153 Sm-HEDTA at these ratios. He concluded that "it is unlikely that effective therapy doses of Sm-153 can be delivered to melanoma tumors by these and similar chelates.” He suggested the use of monoclonal antibodies with 153 Sm. Another attempt to have complexes deliver metal ions to soft tissue tumors was made by Tse et al. in J. Nucl. Med. 30, 202-208 (1989) where they studied 153 Sm-EDTA at a 10 to 1 ligand to metal molar ratio.
• liver uptake and can be used as diagnostic or therapeutic agents.
• the present invention concerns metal-ligand complexes wherein the ligand is an aminocarboxylate containing a phenolic moiety, their formulations, and a method for the therapeutic and/or diagnostic treatment of a mammal having soft tissue tumors.
• the metal-phenolic carboxylate ligand complex of the present invention has as the metal ion 153 Sm, 166 Ho, 90 Y, 159 Gd, 177 Lu, 111 In, 115m In, 175 Yb, 47 Sc, 165 Dy, 52 Fe, 72 Ga, 67 Ga, 68 Ga, Gd , or Fe and has as the ligand a compound of the formula wherein:
• R represents hydrogen, -COOH, R 1 or
• R 1 independently represents hydrogen, C 1 -C 18 alkyl, -Cl, -Br, -I, -N(R 4 ) 2 , -NR 8 C(O)CR 5 R 6 R 7 , -N(OR 5 )C(O)R 6 , - N(O)R 5 R 6 , -NR 5 -NR 6 R 7 , -NR 5 C(O)NR 6 R 7 , -NO 2 , -OR 5 , - OC(O)R 5 , -OC(O)OR 5 , -CN, -SO 3 H, -SO 2 NR 5 R 6 , -NR 5 SO 2 R 6 ,
• R 5 , R 6 , R 7 and R 8 independently represent hydrogen, C 1 -C 18 alkyl, aryl or aryl-C 1 -C 4 alkyl;
• R 2 represents -COOH, -CH 2 OH or -CH(CH 3 )OH;
• R 9 independently represents hydrogen, -COOH
• n is an intereger of 1, 2 or 3; or a pharmaceutically acceptable salt thereof.
• the formulations have the above complexes with a physiologically acceptable liquid carrier.
• the method of the present invention concerns the use of the formulations for the therapeutic and/or diagnostic treatment of a mammal having a soft tissue carcinoma.
• the method of this invention is used for the therapeutic and/or diagnostic treatment of a mammal having soft tissue tumors.
• the compositions used in the method have a radionuclide or metal complexed with a chelating agent.
• a radionuclide or metal complexed with a chelating agent As will be more fully discussed later, the properties of the radionuclide, of the chelating agent and of the complex formed therefrom are important considerations in determining the effectiveness of any particular composition employed for such treatment.
• tumor shall denote a neoplasm, a new abnormal growth of tissue that is not inflammatory, which arises without obvious cause from cells of preexistent tissue, and generally possesses no physiologic function.
• examples may include "carcinomas” which originate from epithelial cells, "sarcomas” of mesodermal (connective tissue) orgin, and lymphomas from the lymphatic system. The origin of the neoplasm is not critical to this
• alkyl includes the straight or branched-chain alkyl moieties, such as methyl, ethyl, isopropyl, n-propyl, n-butyl, t-butyl, n-decyl as well as others.
• aryl includes phenyl, naphthyl, or benzyl.
• aryl-C1-C4 alkyl includes tolyl, or 2,4-dimethylphenyl.
• unsaturated ring has a total of six carbon atoms and is a phenyl or cyclohexyl moiety having one common side of the ring with the phenolic ring.
• complex refers to a chelating agent complexed with a metal ion, preferrably a +3 metal ion, especially a radioactive rare-earth type metal ion, wherein at least one metal atom is chelated or
• radioactive when used in conjunction with the word “metal ion” refers to one or more isotopes of the rare-earth type elements that emit particles and/or photons.
• radiationuclide or “metal” indicates the metal ion.
• complexes of this invention can consist of a formulation having the combination of 1 metal with 1 ligand in the form of a complex and having one or more complexes comprised of a different metal and/or different ligand, present in the same formulation.
• An example of this would be combining one metal ion that is a gamma
• radionuclide for imaging with a ligand and also having present another metal that is a particle emitter for therapy with the same or different ligand.
• the combination of radionuclides may be more efficaious than either radionuclide alone.
• These combinations of complexes may be prepared by administrating two complexes at about the same time to the mammal, or making each complex separately and mixing them prior to use, or mixing the two metal ions with the same ligand and preparing the two or more complexes concurrently.
• the radionuclide used in the complex of the present invention may be suitable for therapeutic, diagnostic or both therapeutic and diagnostic purposes. Examples of the radionuclide used for diagnostic
• radionuclide used for therapeutic purposes are 166 Ho,
• radionuclide used is 153 Sm, 177 Lu, 159 Gd, 175 Yb, or 47 Sc, with 153 Sm, 177 Lu, 175 Yb, 159 Gd being preferred.
• Radionuclides can be produced in several ways.
• a nuclide is bombarded with neutrons to obtain a radionuclide, e.g.
• radionuclides Another method of obtaining radionuclides is by bombarding nuclides with linear accelerator or cyclotron-produced particles. Yet another way of obtaining radionuclides is to isolate them from
• the method of obtaining the radionuclide is not critical to the present invention.
• the desired amount of target is first weighed into a quartz vial, the vial is flame sealed under vacuum and welded into an aluminum can. The can is irradiated for the desired length of time, cooled for several hours and opened remotely in a hot cell. The quartz vial is removed and transferred to a glove box, crushed into a glass vial which is then sealed with a rubber septum and an aluminum crimp cap.
• complexing agent or ligand ( L )
• ligand ( L ) can affect the concentration of species present in solution .
• Competing side reactions can also occur in aqueous solution , thus xM + yOH- ⁇ M M ( OH) y .
• the OH- concentration in solution which is related to pH is, therefore, an important parameter to be considered. If the pH is too high, the metal tends to form metal hydroxides rather than complexes. The complexing agents may also be adversely affected by low pH. Complexation may require the loss of
• a pH in the range of from 5 to 11 is preferred for complexation.
• the chelating agent is a compound of Formula I as defined above, or a pharmaceutically acceptable salt thereof.
• the compounds of Formula I may be prepared readily by methods known to those skilled in the art of organic -synthesis, such as the process shown in
• Suitable bases include, for example, the alkali metal and
• alkaline earth metal hydroxides carbonates
• bicarbonates such as sodium hydroxide, potassium
• Physiologically acceptable salts may be prepared by treating the acid with an appropriate base.
• the metal and ligand may be combined und «r any conditions which allow the two to form a complex.
• Heating was also found in some cases to be useful for dissolving the ligands.
• the appropriate amount of the samarium, or other radionuclide, in the stock solution described above was then added to the ligand solution.
• the pH of the resulting solution was then adjusted to the appropriate level (usually 7-8).
• the complex used in this invention may be a mixture of the different metals as described under the complex term before. In the method of this invention, it is preferred to employ the complex in the presence of an excess of ligand.
• the ligand to metal ratio (L:M) of the ligand to radionuclide or metal is at least 1:1.
• the upper limit of L:M depends on the toxicity of the ligand or the specific activity of the radionuclide.
• the preferred range for the L:M ratio is at least 1:1, preferrably from 1:1 to about 600:1, more preferably from 1:1 to about 300:1, most preferrably from about 100:1 to about 300:1.
• the upper L:M range could be significantly higher, such as 5 ⁇ 10 7 :1.
• mammary glands preferably warm blooded mammals, more preferably humans.
• salts means any salt of a compound of formula (I) which is sufficiently non-toxic to be useful in therapy or diagnosis of mammals.
• the salts are useful in accordance with this invention.
• Representative of those salts, which are formed by standard reactions, from both organic and inorganic sources include, for example, sulfuric, hydrochloric, phosphoric, acetic, succinic, citric, lactic, maleic, fumaric, palmitic, cholic, palmoic,. mucic, glutamic, d-camphoric, glutaric,
• salts formed by standard reactions from both organic and inorganic sources such as ammonium, alkali metal ions, alkaline earth metal ions, and other similar ions. Particularly preferred are the salts of the compounds of formula (I) where the salt is potassium, sodium, ammonium, or mixtures
• formulations of the present invention are in the solid or liquid form containing the active radionuclide complexed with the ligand.
• formulations may be in kit form such that the two components (i.e. ligand and metal) are mixed at the appropriate time prior to use. Whether premixed or as a kit, the formulations usually require a pharmaceutically acceptable carrier.
• Injectable compositions of the present invention may be either in suspension or solution form.
• a physiologically acceptable carrier comprise a suitable solvent, preservatives such as benzyl alcohol, if needed, and buffers.
• Useful solvents include, for example, water, aqueous alcohols, glycols, and phosphate or carbonate esters. Such aqueous solutions contain no more than 50 percent of the organic solvent by volume.
• Injectable suspensions are compositions of the present invention that require a liquid suspending medium, with or without adjuvants, as a carrier.
• the suspending medium can be, for example, aqueous
• polyvinylpyrrolidone inert oils such as vegetable oils or highly refined mineral oils, or aqueous
• Suitable physiologically acceptable adjuvants may be chosen from among thickeners such as carboxymethylcellulose, polyvinylpyrrolidone,
• surfactants are also useful as suspending agents, for example, lecithin, alkylphenol, polyethylene oxide adducts,
• hydrophilicity, density, and surface tension of the liquid suspension medium can assist in making injectable suspensions in individual cases.
• silicone antifoames, sorbitol, and sugars are all useful
• an “effective amount” of the formulation is used for therapy.
• the dose will vary depending on the disease being treated.
• in vitro diagnostics can be performed with the formulations of this invention, in vi ⁇ o diagnostics are also contemplated using formulations of this invention.
• the invention described herein provides a means of delivering a therapeutic amount of radioactivity to soft tissue tumors. However, it may also be desirable to administer a "sub-therapeutic" amount to determine the fate of the radionuclide using a scintillation camera prior to administering a
• Therapeutic doses will be administered in sufficient amounts to reduce pain and/or inhibit tumor growth and/or cause regression of tumors and/or kill the tumor. Amounts of radionuclide needed to provide the desired therapeutic dose will be determined
• composition The amount of radioactivity required to deliver a therapeutic dose will vary with the individual composition employed.
• administered may be given in a single treatment or fractionated into several portions and administered at different times. Administering the composition in fractionated doses may make it possible to minimize damage to non-target tissue. Such multiple dose
• administration may be more effective.
• compositions of the present invention may be used in conjunction with other active agents and/or ingredients that enhance the therapeutic effectiveness of the compositions and/or facilitate easier
• the present invention provides a complex which allows a radionuclide to localize in the tumor and displays low radionuclide uptake in other tissues, e.g. liver.
• Bis-IDA 2,6-bis[N,N-bis(carboxymethyl)- aminomethyl]-4-(acetamido)phenol
• Bis-IDA-NH 2 2, 6-bis[N,N-bis ( carboxymethyl ) - aminomethyl]-4-(amino)phenol
• Gd Gadolinium
• chelant is equivalent to ligand
• Example B Preparation of Mono-IDA Into a flask equipped with a water-cooled reflux condenser, mechanical stirrer, therometer with a temperature controller, and addition funnel, was added 35.3 G of deionized water, 35.3 G (0.26 mole) of 89% IDA, and 39.9 G of 50% aqueous NaOH. The mixture was heated, with stirring, to a temperature of 55°C.
• Aqueous 37% formaladehde solution 21.5 G (0.27 mole) was placed in the addition funnel and added to the mixture over 15 minutes. The mixture was heated at 55°C for 45 minutes, cooled and transferred to an addition funnel. To a 500 mL flask, equiped as before, was added 38.7 G (0.25 mole) of 98% 4-acetamidophenol, 35.3 G of deionized water, and 12.2 G of 50% aqueous NaOH
• Bis-IDA, 43.0 mG was weighed into a 5 mL glass vial and 2.38 mL of a 3 ⁇ 10 -4 M solution of SmCl 3 in 0.1M HCl and 0.62 mL of a 3 ⁇ 10 -4 M solution of 153 SmCl 3 in 0.1M HCl was added. The pH was adjusted to 7-8 using 50% NaOH. The activity of the final solution was about 3.5 mCi in about 3.0 mL with a ligand to metal ratio of about 300:1.
• Mono-IDA, 90.0 mG was weighed into a 5 mL glass vial and 2.5 mL of a 3 ⁇ 10 -4 M solution of SmCl 3 in 0.1M HCl and 0.5 mL of 3 ⁇ 10 -4 M solution of SmCl 3 in 0.1M HCl was added. The pH was adjusted to 7-8 using 50% NaOH. The activity of the final solution was about
• Bis-IDA, 28.6 mG was weighed into a 5 mL glass vial and 2.0 mL of a 3 ⁇ 10 -4 M solution of SmCl 3 in 0.1M HCl and containing a tracer amount of 153 Sm. The pH was raised to 13-14 using 50% NaOH. The pH was then
• the activity of the final solution was about 2 mCi/mL with a ligand to metal ratio of 100: 1.
• Example 4 Bis-IDA, 5.7 mG, was weighed into a 5 mL glass vial and 2.0 mL of a 3 ⁇ 10 -4 M solution of SmCl 3 in 0.1M HCl and and containing a tracer amount of 153 Sm. The pH was adjusted to 7-8 by the procedure described in
• Example 3 The activity of the final solution was about 4 mCi in about 2 mL with a ligand to metal ratio of 20:1.
• Bis-IDA-NH 2 117.7 mG
• a 5 mL glass vial 2.0 mL of a 3 ⁇ 10 -4 M solution of SmCI 3 in 0.1M HCl and and containing a tracer amount of 153 Sm.
• the pH was adjusted to 7 using NaOH solution (85 ⁇ L of 50% NaOH).
• the activity of the final solution was about 2 mCi in about 1 mL with a ligand to metal ratio of 300:1.
• the yellow solution was quantitatively transferred to a 50 mL volumetric flask and brought to volume with deionized water.
• the solution was filtered through a 0.22 ⁇ m filter into a 100 mL beaker.
• This solution was dispensed ionto 10 mL serum vials (2.3 mL in each vial).
• Each vial contained 0.54 mmol of Bis-IDA and 2.043 mmol of NaOH. Twenty vials were filled, the contents frozen and freeze-dried, then sealed under vacuum to form kits.
• the sample solution used for injection was from 0.5-1mL containing 1-2 mCi of 1 53 Sm.
• the pigs had whole body counts immediately after injection and again at 24, 48 and 72 hours. Images (right lateral, left lateral and dorsal) were made at 4, 24, 48 and 72 hours.
• the 24 hour images were evaluated independently by 3 investigators for the uptake of 153 Sm in bone, liver and tumor.
• the following scheme was used for scaling the uptake of 153 Sm in the various tissues:
• Ga-citrate never cleared the extracellular fluid and had an unacceptably large liver uptake.
• a poodle dog with an oral melanoma on the left mandible that had metastasized to a regional lymph node was treated with about 3 mCi of 153 Sm from a reconstituted kit of Example 6.
• a Scottie dog with a surgically removed recurrent melanoma on the left side was treated with about 3 mCi of 153 Sm from a reconstituted kit of Example 6.

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