WO2001052900A2 - Nouveaux chelateurs d'acides amines a protection orthogonale pour des applications biomedicales - Google Patents

Nouveaux chelateurs d'acides amines a protection orthogonale pour des applications biomedicales Download PDF

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WO2001052900A2
WO2001052900A2 PCT/US2001/001903 US0101903W WO0152900A2 WO 2001052900 A2 WO2001052900 A2 WO 2001052900A2 US 0101903 W US0101903 W US 0101903W WO 0152900 A2 WO0152900 A2 WO 0152900A2
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bis
aryl
alkyl
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WO2001052900A3 (fr
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Samuel I. Achilefu
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Mallinckrodt Inc
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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
    • A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
    • A61K51/04—Organic compounds
    • A61K51/0474—Organic compounds complexes or complex-forming compounds, i.e. wherein a radioactive metal (e.g. 111In3+) is complexed or chelated by, e.g. a N2S2, N3S, NS3, N4 chelating group
    • A61K51/0482—Organic compounds complexes or complex-forming compounds, i.e. wherein a radioactive metal (e.g. 111In3+) is complexed or chelated by, e.g. a N2S2, N3S, NS3, N4 chelating group chelates from cyclic ligands, e.g. DOTA
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/62—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being a protein, peptide or polyamino acid
    • 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
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
    • A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
    • A61K51/04—Organic compounds
    • A61K51/08—Peptides, e.g. proteins, carriers being peptides, polyamino acids, proteins
    • A61K51/083—Peptides, e.g. proteins, carriers being peptides, polyamino acids, proteins the peptide being octreotide or a somatostatin-receptor-binding peptide
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
    • A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
    • A61K51/04—Organic compounds
    • A61K51/08—Peptides, e.g. proteins, carriers being peptides, polyamino acids, proteins
    • A61K51/088—Peptides, e.g. proteins, carriers being peptides, polyamino acids, proteins conjugates with carriers being peptides, polyamino acids or proteins
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    • 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
    • C07C233/45—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 carboxyl groups
    • C07C233/46—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 carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom
    • C07C233/47—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 carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom having the carbon atom of the carboxamide group bound to a hydrogen atom or to a carbon atom of an acyclic saturated carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C271/00—Derivatives of carbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
    • C07C271/06—Esters of carbamic acids
    • C07C271/08—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms
    • C07C271/10—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C271/16—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms to carbon atoms of hydrocarbon radicals substituted by singly-bound oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C271/00—Derivatives of carbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
    • C07C271/06—Esters of carbamic acids
    • C07C271/08—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms
    • C07C271/10—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C271/20—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms to carbon atoms of hydrocarbon radicals substituted by nitrogen atoms not being part of nitro or nitroso groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C275/00—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups
    • C07C275/04—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to acyclic carbon atoms
    • C07C275/06—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to acyclic carbon atoms of an acyclic and saturated carbon skeleton
    • C07C275/16—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to acyclic carbon atoms of an acyclic and saturated carbon skeleton being further substituted by carboxyl groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C275/00—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups
    • C07C275/46—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups containing any of the groups, X being a hetero atom, Y being any atom, e.g. acylureas
    • C07C275/58—Y being a hetero atom
    • C07C275/62—Y being a nitrogen atom, e.g. biuret
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D257/00—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms
    • C07D257/02—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/575—Hormones
    • C07K14/655—Somatostatins
    • C07K14/6555—Somatostatins at least 1 amino acid in D-form
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
    • C07K7/04—Linear peptides containing only normal peptide links
    • C07K7/08—Linear peptides containing only normal peptide links having 12 to 20 amino acids
    • C07K7/086—Bombesin; Related peptides
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2603/00—Systems containing at least three condensed rings
    • C07C2603/02—Ortho- or ortho- and peri-condensed systems
    • C07C2603/04—Ortho- or ortho- and peri-condensed systems containing three rings
    • C07C2603/06—Ortho- or ortho- and peri-condensed systems containing three rings containing at least one ring with less than six ring members
    • C07C2603/10—Ortho- or ortho- and peri-condensed systems containing three rings containing at least one ring with less than six ring members containing five-membered rings
    • C07C2603/12—Ortho- or ortho- and peri-condensed systems containing three rings containing at least one ring with less than six ring members containing five-membered rings only one five-membered ring
    • C07C2603/18—Fluorenes; Hydrogenated fluorenes

Definitions

  • This invention relates to polyazacarboxylates and their peptide conjugates which are useful for imaging, diagnosis and therapy. Particularly, this invention relates to compositions of two or more peptides that are conjugated to a molecule of polyazacarboxylate ligand.
  • the compounds of this invention have the general formula:
  • R,NHC(O)-LS-C(O)NHR 2 Formula 1 wherein R, and R 2 are peptides with the same or different receptor affinities and LS is a cyclic or linear polyazacarboxylates. They are useful for therapeutic and contrast agents in biomedical applications.
  • the tumors can then be visualized and destroyed by agents that target the receptors which are over-expressed in the given tumor (J. E. Bugaj, J. L. Erion, M. A. Schmidt, R. R. Wilhelm, S. I. Achilefu, A. Srinivasan, Biodistribution and Radiotherapy Studies Using Samarium- 153 and Lutetium-177 DTPA Conjugates of Y 3 - Octreotate. Journal. Nuclear Medicine., 1999, 40(5), 223P).
  • This site-specific delivery of contrast agents enables the differentiation of normal from diseased tissues and also preserves normal tissues from lethal therapeutic drugs.
  • a current method for tumor imaging involves the conjugation of radioactive metal chelates to antibodies or peptides that target the abundant receptors on a given tumor (R. Albert, E. P. Krenning, S. W. J. Lamberts, and J. Pless, Use of certain somatostatin peptides for the in vivo imaging of somatostatin receptor-positive tumors and metastasis. US 5,753,627). Careful selection of metals and peptides determines the imaging modality and therapeutic potential of the chelate-peptide conjugate. For example, gadolinium chelates are used for magnetic resonance imaging (A. D. Nunn, K. E. Linder, and M. F. Tweendle, Can receptors be imaged with MRI agent?
  • radioactive metals are used for scintigraphy (e.g. technetium-99, indium- 111, see A. Srinivasan, M. M Dyszlewski,
  • Reubi The role of somatostatin and its analogs in the diagnosis and treatment of tumors. Endocrine Reviews, 1991, 12(4), 450-478) can function as both delivery and therapeutic agents.
  • the metal chelates are attached to free amino groups of antibodies and peptides (R. Albert, E. P. Krenning, S. W. J. Lamberts, and J. Pless, Use of certain somatostatin peptides for the in vivo imaging of somatostatin receptor-positive tumors and metastasis. US 5,753,627).
  • a single tumor line may over-express more than one class receptors (for example, breast tumor may overexpress either estrogen, somatostatin or bombesin receptors) and the receptor density may vary from one patient to another (S. W. J. Lamberts, E. P. Krenning, and J. C. Reubi, The role of somatostatin and its analogs in the diagnosis and treatment of tumors. Endocrine Reviews, 1991, 12(4), 450-478; S. R. Preston, G. V. Miller, and J. M. Primrose, Bombesin-like peptides and cancer. Critical Reviews in Oncology/Hematology, 1996, 23, 225-238).
  • the conventional method of attaching a metal chelate to a tumor targeting group could lead to many false negatives which could lead to deaths.
  • a logical approach to solving this problem involves the administration of a cocktail of chelate-metal conjugates to the patient. While this method may improve diagnosis, it will require the synthesis and development of several peptide-chelate conjugates which will drastically increase the cost of health care. Also, dose formulation would become a major problem because of possible incompatibilities of such mixtures. Further, isolation of the cause of any observed side-effect would become an arduous task for the physician. Finally, a minimum radiation dose is usually required for the detection of radioactive markers in tissues. Each component of the cocktail must, therefore, contain this threshold of radioactivity. Hence, the net radiation dose administered to the patient would be unacceptable.
  • a better approach would be to incorporate two or more peptides that have high affinity for the most common receptors in a given diseased state. This would require a linker to combine the peptides into one molecule.
  • a ligand is required to chelate the metal radionuclide of interest.
  • Dunn and Srinivasan described a method for incorporating ligand precursors into peptides (US Patent 5,798,444 and US Patent 5,734,011). However, their method only introduces a ligand precursor and requires elaborate chemistries on solid support to complete the ligand synthesis.
  • the present invention relates particularly to the novel composition comprising polyazacarboxylates of the formula 1 or la:
  • R, to R 4 may be the same or different and are selected from the group consisting of alkyl, aryl, heterocarbocyclic, NH-k-NHR 30 , CH 2 CO 2 H, hydroxyl, amino, C1-C10 alkoxyl, C1-C10 aryloxyl, C1-C10 polyalkoxyalkyl, -CH ⁇ CH ⁇ -CH ⁇ -CH ⁇ R,, C1-C20 polyhydroxyalkyl, Cl- C10 polyhydroxyaryl, or X-Y; W is selected from the group consisting of alkyl, aryl, -CH 2 (CH 2 - O-CH j CH ⁇ R a , polyhydroxyalkyl, or polyhydroxyaryl; X is selected from the group consisting of -NH, -CONH-, -CH 2 NH-, -CH 2 NR 5 -, -COO-, -O-, -C(O)-, -S-, -NHCO-, or -
  • the present invention also relates to novel compositions comprising a polyazacarboxylate of the formula 2 or 2a:
  • Rg to R 10 are defined in the same manner as R, to R 4 ;
  • X 2 and Y 2 are defined in the same manner as X and Y respectively;
  • W 2 and W 3 are as defined for W;
  • z varies from 1-10, preferably 1-3.
  • the present invention also relates to novel compositions comprising a polyazacarboxylate of the formula 3:
  • R, , to R 15 are defined in the same manner as R, to R 4 ; X 3 and Y 3 are defined in the same manner as X and Y, respectively; W 4 and W 5 are as defined for W; and W )8 is as defined for W 15 .
  • the present invention also relates to novel compositions comprising a polyazacarboxylate of the formula 4:
  • the present invention also relates to a method of preparing a carboxyl-terminal chelator composition comprising polyazacarboxylates of the formula 4:
  • This invention is also related to the methods of preparing any of the composition of formulas 1 to 4.
  • compositions of the present invention comprising polyazacarboxylates of formulas 1 to 4 offer significant advantages over those currently described in the art.
  • the chelators are designed to either mimic the reactivity of amino acids or they possess at least one free dicarboxylic acid group on the same molecule. This ensures the rapid attachment of two or more different bioactive peptides on the same molecule.
  • each chelating group is designed to assure in vivo stability on conjugating two or more peptides.
  • the synthetic procedures described in this invention are amenable to either solid or solution phase synthesis and are compatible with combinatorial synthesis of an array of products. Further, the compounds of this invention are compatible with automated organic synthesis procedures. These compositions are particularly useful when one peptide requires a free amino terminus and the other peptide requires a free carboxyl terminus for their bioactivity.
  • polyazacarboxylic acid bis-peptide conjugates according to the present invention have the general formula 5:
  • each R 20 is H, t-butyl or benzyl;
  • L, and L 2 may be the same or different and may be a single bond or are taken from the group consisting of -(CH 2 ) t -NHC(O)- or -CH 2 -(CH 2 -O-CH 2 ) u - NHC(O)-;
  • t varies from 1 to 10;
  • u varies from 1 to 50;
  • z varies from 1 to 10, preferably from 1 to 3.
  • Peptide, and Peptide 2 have affinities toward the same or different tumor receptors.
  • polyazacarboxylic acid bis-peptide conjugates according to the present invention have the general formula 6:
  • R 20 , Ldon j, Peptide,, and Peptide 2 are as defined in formula 5;
  • W 8 to W, 0 may be the same or different and may be selected from the group consisting of (CH 2 ) h or (CH ⁇ H ) i wherein h varies from 1 to 10 and j varies from 1 to 50;
  • W 20 is defined as W, 7 ; and
  • z varies from 1 to 10, preferably from 1 to 3.
  • polyazacarboxylic acid bis-peptide conjugates according to the present invention have the general formula 7:
  • R 20 , Ldon L 2 , Peptide,, and Peptide 2 are as defined in formula 5; W,, to W 13 are as defined for W 8 to W 10 ; and W 2 , is as defined for W, 7 .
  • polyazacarboxylic acid bis-peptide conjugates according to the present invention have the general formula 8:
  • R 20 , L tolerate L 2 , Peptide,, and Peptide 2 are as defined in formula 5; W I4 to W 16 are as defined for W 8 to W, 0 ; and W 22 is as defined for W, 7 .
  • the invention also relates to the location of the multi -bioactive peptides on any R 20 as amide derivatives.
  • the invention includes methods for synthesizing intermediates and compounds of the formulas 1 to 4 as illustrated in schemes 1 to 14.
  • the invention also includes the use of the formulations disclosed herein for the synthesis of a combinatorial library of compounds.
  • n+ T -O- or -NH-
  • compositions of the invention can be formulated into diagnostic compositions for enteral or parenteral aclministration. These compositions contain an effective amount of the dye along with conventional pharmaceutical carriers and excipients appropriate for the type of administration contemplated.
  • parenteral formulations advantageously contain a sterile aqueous solution or suspension of dye according to this invention.
  • Parenteral compositions may be injected directly or mixed with a large volume parenteral composition for systemic administration.
  • Such solutions also may contain pharmaceutically acceptable buffers and, optionally, electrolytes such as sodium chloride.
  • Formulations for enteral administration may vary widely, as is well known in the art. In general, such formulations are liquids which include an effective amount of the dye in aqueous solution or suspension. Such enteral compositions may optionally include buffers, surfactants, thixotropic agents, and the like. Compositions for oral administration may also contain flavoring agents and other ingredients for enhancing their organoleptic qualities.
  • the diagnostic compositions are administered in doses effective to achieve the desired enhancement. Such doses may vary widely, depending upon the particular dye employed, the organs or tissues which are the subject of the imaging procedure, the imaging equipment being used, and the like.
  • the diagnostic compositions of the invention are used in the conventional manner.
  • the compositions may be administered to a patient, typically a warm-blooded animal, either systemically or locally to the organ or tissue to be imaged, and the patient is then subjected to the imaging procedure.
  • the reaction mixture was partitioned between 100 ml of methylene chloride and 100 ml of saturated sodium bicarbonate solution. The layers were separated and the methylene chloride layer was again washed with 100 ml of saturated sodium bicarbonate solution. The combined aqueous layers were extracted twice with 25 ml of methylene chloride. The combined methylene chloride layers were washed with 100 ml of brine, and dried over magnesium sulfate. The methylene chloride was removed with aspirator vacuum at ca. 35°C, and the remaining dimethylformamide was removed with vacuum at about 45°C. The crude material was left on a vacuum line overnight at room temperature.
  • the ether solution was decanted and the oil was again triturated with a 100 ml portion of ether.
  • the ether was decanted and the combined ether solutions allowed to stand for about 2 hours to allow the triphenylphosphine oxide to crystallize.
  • the ether solution was decanted from the crystals and the solid washed with 100 ml of ether.
  • the volume of the combined ether abstracts was reduced with vacuum until a volume of about 25 ml was obtained. This was allowed to stand overnight at 0°C.
  • Ether (10 ml) was added to the cold mixture which was mixed to suspend the solid. The mixture was percolated through a column of 45 g of silica gel and eluted with ether, and 75 ml fractions were collected.
  • the reaction mixture was partitioned between 700 ml of methylene chloride and 700 ml of saturated sodium bicarbonate solution. The layers were separated and the methylene chloride layer was again washed with 700 ml of saturated sodium bicarbonate solution. The combined aqueous layers were extracted twice with 200 ml of methylene chloride. The combined methylene chloride layers were washed with 500 ml of brine, and dried over magnesium sulfate. The methylene chloride was removed with aspirator vacuum at ca. 35°C, and the remaining dimethylformamide was removed with vacuum at about 45°C. The crude material was left on a vacuum line overnight at room temperature.
  • the ether solution was decanted and the oil was again triturated with a 500 ml portion of ether.
  • the ether was decanted and the combined ether solutions allowed to stand for about 2 hours to allow the triphenylphosphine oxide to crystallize.
  • the ether solution was decanted from the crystals and the solid washed with 500 ml of ether.
  • the volume of the combined ether abstracts was reduced with vacuum until a volume of about 80 ml was obtained. This was allowed to stand over night at 0°C.
  • Ether 100 ml was added to the cold mixture which was mixed to suspend the solid. The mixture was filtered and washed ten times with 4 ml of ether.
  • Method A a mixture of N,N-bis(t-butyloxycarbonylmethyl) benzylamine (5 g, 14.8 mmol), ammonium formate (2.4 g) and 10% Pd-C (1 g) in methanol (50 mL) was refluxed for 30 minutes. Upon cooling to ambient temperature, the catalyst was filtered over celite and the cake was washed with methanol. The solvent was evaporated and the residue extracted with chloroform. Filtration of the extract and evaporation of the solvent gave the pure secondary amine (3.4 g, 94%) as an oil.
  • Method B a mixture of N,N-bis(t-butyloxycarbonylmethyl) benzylamine (6 g, 19.5 mmol) and 10% Pd-C (0.6 g) in methanol (60 mL) was hydrogenolyzed at 45 psi for 2 hours.
  • N,N,N-dibenzylethanolamine was brominated with triphenylphosphine and N- bromosuccinimide as described in Example 1.
  • the aqueous phase was decanted and the sticky product was dissolved in toluene and washed thrice with water.
  • the organic layer was dried over MgSO 4 and the solvent was evaporated.
  • the crude intermediate product was purified by flash chromatography to give the monotrityl tetraethyleneglycol intermediate (12.7 g, 80% yield) as pale yellow oil.
  • the monotrityl tetraethyleneglycol (28 mmol)) was dissolved in anhydrous dichloromethane (200 mL) and cooled to -20 °C. After addition of triethyl amine (36.75 mmol), methanesulfonyl chloride (35 mmol) was introduced dropwise.
  • the monotrityl N,N-dibenzylaminohexaethyleneglycol was hydrogenated to give the ⁇ , ⁇ - aminoalcohol of hexaethyleneglycol.
  • the primary amine was tritylated with trityl chloride and bromination of the primary alcohol was- carried out with triphenylphosphine and NBS as described in Example 1.
  • N,N-benzyloxycarbonylmemyl-t-butyloxycarbonylmemylaminoethyl bromide (17; 22 mmol) as described in Example 17.
  • Catalytic hydrogenation of the product with 10% Pd-C catalyst and subsequent protection of the free amine with Fmoc-succinimide yields the desired compound which can be purified by flash chromatography.
  • the product is prepared as described in Example 23 starting with benzyl diethylenetriamine .
  • the two layers formed were separated and the organic phase was washed with water (200 ml) and brine (200 ml) in that order.
  • the dichloromethane layer was dried over magnesium sulfate and the solvent was removed in vacuo to give a viscous liquid residue which was dissolved in hexane and purified by dry flash chromatography with 20% diethyl ether in hexane to give the pure compound (65%) as a pale yellow liquid.
  • the benzylester was removed by catalytic hydrogenation in methanol (200 mL) with 10% palladium on carbon (0.4 g) at 50 psi for 1 hour. The mixture was filtered over celite and the residue was washed with methanol (2 x 50 ml). The solvent was evaporated to give the pure product .
  • Example 17 gives the dibenzyl ester which was hydrogenolyzed as described in Example 18.
  • EXAMPLE 33 Synthesis of
  • Example 34 The procedure for the conjugation of the mono-Fmoc ethylenediamine with the dicarboxylic acid of Example 34 is the same as in Example 22.
  • X COOH;
  • the amino auds and tri- t-butyl DTPA cartridges were placed on the peptide synthesizer and the product was synthesized from the C-terminal to the N-terminal position.
  • the free acid from tri-t-butyl DTPA was activated on solid support with HBTU/HOB (1.5 equiv.) for 30 minutes and mono-Fmoc ethylenediamine (3 equiv.) was added in the presence of diisopropylethylamine (3 equiv.). The mixture was shaken for 2 hours and the resin was washed with DMF and THF.
  • the resin After drying the resin, it was placed on the resin cartridge and the second peptide (bombesin (7-14) was synthesized automatically. At the end of the reaction, the disulfide bond was formed between the two Cysteines of the octreotate peptide with thallium trifluoroacetate.
  • the product was cleaved from the solid support with a cleavage mixture containing trifluoroacetic acid (85%):water (5%):phenol (5%):thioanisole (5%) for 6 hours. Note that the t-butyl esters of tri-t-butyl DTPA were also cleaved to give the free tetra-carboxylic acid.
  • the DTPA-bispeptide conjugate was precipitated with t-butyl methyl ether and lyophilized with water : acetonitrile (2/3) mixture.
  • the crude product was purified by HPLC to give the desired product as shown by mass spectral analysis.
  • X COOH;
  • the 115 In -DTPA-bispeptide complex was prepared by reacting the DTPA-bispeptide (50 mmol) with 115 InCl 3 (90 mmol) in 170 ⁇ L of aqueous HCl (5 nM) at room temperature for 30 minutes. The solution was neutralized lyophilized and purified by HPLC to obtain the desired compound.

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  • Peptides Or Proteins (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
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Abstract

L'invention concerne des polyazacarboxylates et leurs conjugués peptidiques, utiles dans l'imagerie, le diagnostic et la thérapie. L'invention concerne plus spécialement des compositions d'au moins deux peptides qui sont conjugués à une molécule de ligand polyazacarboxylate. Les composés de l'invention sont de formule générale (1): R1NHC(O)-LS-C(O)NHR2 dans laquelle R1 et R2 sont des peptides ayant des affinités de récepteur identiques ou différentes, et LS est un polyazacarboxylate cyclique ou linéaire. Les composés sont utiles pour des agents thérapeutiques ou de contraste dans des applications biomédicales.
PCT/US2001/001903 2000-01-21 2001-01-18 Nouveaux chelateurs d'acides amines a protection orthogonale pour des applications biomedicales Ceased WO2001052900A2 (fr)

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AU2001236485A AU2001236485A1 (en) 2000-01-21 2001-01-18 Novel orthogonally protected amino acid chelators for biomedical applications

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US17721700P 2000-01-21 2000-01-21
US60/177,217 2000-01-21

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Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003009874A1 (fr) * 2001-07-20 2003-02-06 Schering Ag Complexes metalliques macrocycliques et leur utilisation pour la production de composes conjugues avec des biomolecules
FR2891830A1 (fr) * 2005-10-07 2007-04-13 Guerbet Sa Composes a chaines aminoalcools courtes et complexes metalliques pour l'imagerie medicale
EP1585549A4 (fr) * 2003-01-13 2009-07-29 Bracco Imaging Spa Composes de peptide liberant la gastrine
US7611692B2 (en) 2003-01-13 2009-11-03 Bracco Imaging S.P.A. Gastrin releasing peptide compounds
US7850947B2 (en) 2003-01-13 2010-12-14 Bracco Imaging S.P.A. Gastrin releasing peptide compounds
US7922998B2 (en) 2003-01-13 2011-04-12 Bracco Imaging S.P.A. Gastrin releasing peptide compounds
US8420050B2 (en) 2003-01-13 2013-04-16 Bracco Imaging S.P.A. Gastrin releasing peptide compounds
US8926945B2 (en) 2005-10-07 2015-01-06 Guerbet Compounds comprising a biological target recognizing part, coupled to a signal part capable of complexing gallium
US8986650B2 (en) 2005-10-07 2015-03-24 Guerbet Complex folate-NOTA-Ga68
CN109153635A (zh) * 2016-04-04 2019-01-04 研究三角协会 神经肽s受体(npsr)激动剂
CN115515927A (zh) * 2021-05-06 2022-12-23 斯微(上海)生物科技股份有限公司 一种脂质
EP4653016A1 (fr) 2023-01-17 2025-11-26 SystImmune, Inc. Conjugué de médicament d'éribuline

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Publication number Priority date Publication date Assignee Title
US5057302A (en) * 1987-02-13 1991-10-15 Abbott Laboratories Bifunctional chelating agents
US5094950A (en) * 1988-06-07 1992-03-10 Nihon Medi-Physics Co., Ltd. Diethylenetriamine pentaacetic acid derivatives
DE3920358A1 (de) * 1989-06-22 1991-01-17 Behringwerke Ag Bispezifische und oligospezifische, mono- und oligovalente antikoerperkonstrukte, ihre herstellung und verwendung
US5154914A (en) * 1990-03-12 1992-10-13 Research Corporation Technologies, Inc. Methods of diagnostic image analysis using lipophilic contrast agents
ES2126695T3 (es) * 1993-10-22 1999-04-01 Nihon Mediphysics Co Ltd Peptido que tiene afinidad hacia la inflamacion y medio diagnostico radiactivo que lo contiene.
IL116500A0 (en) * 1995-12-21 1996-03-31 Yeda Res & Dev Derivatives of avidin-type molecules and pharmaceutical compositions comprising them
WO2000058269A1 (fr) * 1999-03-26 2000-10-05 Mallinckrodt Inc. Esters dtpa avec groupes de protection amovibles orthogonaux

Cited By (25)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003009874A1 (fr) * 2001-07-20 2003-02-06 Schering Ag Complexes metalliques macrocycliques et leur utilisation pour la production de composes conjugues avec des biomolecules
US7164016B2 (en) 2001-07-20 2007-01-16 Schering Ag Macrocyclic metal complexes and their use for the production of conjugates with biomolecules
US8414864B2 (en) 2003-01-13 2013-04-09 Bracco Imaging S.P.A. Gastrin releasing peptide compounds
JP4836455B2 (ja) * 2003-01-13 2011-12-14 ブラッコ・イメージング・ソシエタ・ペル・アチオニ 改善されたガストリン関連ペプチド化合物
EP1585549A4 (fr) * 2003-01-13 2009-07-29 Bracco Imaging Spa Composes de peptide liberant la gastrine
US7611692B2 (en) 2003-01-13 2009-11-03 Bracco Imaging S.P.A. Gastrin releasing peptide compounds
JP2010116415A (ja) * 2003-01-13 2010-05-27 Bracco Imaging Spa 改善されたガストリン関連ペプチド化合物
US7850947B2 (en) 2003-01-13 2010-12-14 Bracco Imaging S.P.A. Gastrin releasing peptide compounds
US7922998B2 (en) 2003-01-13 2011-04-12 Bracco Imaging S.P.A. Gastrin releasing peptide compounds
US8420050B2 (en) 2003-01-13 2013-04-16 Bracco Imaging S.P.A. Gastrin releasing peptide compounds
US8420053B2 (en) 2003-01-13 2013-04-16 Bracco Imaging S.P.A. Gastrin releasing peptide compounds
US8444954B2 (en) 2003-01-13 2013-05-21 Bracco Imaging S.P.A. Gastrin releasing peptide compounds
US8114863B2 (en) 2005-10-07 2012-02-14 Guerbet Compounds comprising short aminoalcohol chains and metal complexes for medical imaging
FR2891830A1 (fr) * 2005-10-07 2007-04-13 Guerbet Sa Composes a chaines aminoalcools courtes et complexes metalliques pour l'imagerie medicale
WO2007042506A1 (fr) * 2005-10-07 2007-04-19 Guerbet Composés comprenant des chaînes aminoalcool courtes et des complexes métalliques en imagerie médicale
EP2457914A1 (fr) * 2005-10-07 2012-05-30 Guerbet Composés comprenant des chaînes d'amino-alcool courtes et des complexes métalliques pour l'imagerie médicale
US8926945B2 (en) 2005-10-07 2015-01-06 Guerbet Compounds comprising a biological target recognizing part, coupled to a signal part capable of complexing gallium
US8986650B2 (en) 2005-10-07 2015-03-24 Guerbet Complex folate-NOTA-Ga68
CN109153635A (zh) * 2016-04-04 2019-01-04 研究三角协会 神经肽s受体(npsr)激动剂
JP2019513704A (ja) * 2016-04-04 2019-05-30 リサーチ トライアングル インスティテュート ニューロペプチドｓ受容体（ｎｐｓｒ）アゴニスト
EP3440051A4 (fr) * 2016-04-04 2019-11-27 Research Triangle Institute Agonistes du récepteur du neuropeptide s (npsr)
AU2017246706B2 (en) * 2016-04-04 2020-09-17 Research Triangle Institute Neuropeptide s receptor (NPSR) agonists
US11142546B2 (en) 2016-04-04 2021-10-12 Research Triangle Institute Neuropeptide S receptor (NPSR) agonists
CN115515927A (zh) * 2021-05-06 2022-12-23 斯微(上海)生物科技股份有限公司 一种脂质
EP4653016A1 (fr) 2023-01-17 2025-11-26 SystImmune, Inc. Conjugué de médicament d'éribuline

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