Bracco Imaging S.p.a.

Enrico Cappelletti

Luciano Lattuada

Rolf E Swenson

Karen E Linder

Michael F Tweedle

Edmund R Marinelli

Palaniappa Nanjappan

Natarajan Raju

Kondareddiar Ramalingam

Pier Lucio Anelli

Marino Brocchetta

Adrian D Nunn

Giovanna Lux

Carlo Felice Viscardi

Christoph De Haen

Mario Virtuani

Sonia Gazzetto

Laura Galimberti

Ornella Gazzotti

Andrea Beltrami

Loredana Sini

Mary Ellen Maddalena

The present invention relates to a process for the preparation of 5-[(2-hydroxyacyl)amino]-2,4,6-triiodo-1,3-benzendicarboxamidic derivatives comprising the Smiles rearrangement of a suitable precursor, by contact of an aqueous solution of this latter with an anion exchanger solid phase.

Process for the preparation of contrast agents

The present invention generally refers to a process for the preparation of L-thyroxine derivatives. More in particular, the present invention relates to a iodination reaction of an aromatic derivative with an appropriate iodinating agent, so to afford the related iodinated compound as disodium salt, which may represent a useful intermediate for the synthesis of the L-thyroxine mono-sodium salt, and the free form thereof.

Process for the preparation of thyroid hormones and salts thereof

New and improved compounds for use in diagnostic imaging or therapy having the formula M-N&#x2014;O&#x2014;P-G, wherein M is a metal chelator having the structure: wherein R1-R5 and FG are as defined herein (in the form complexed with a metal radionuclide or not), N&#x2014;O&#x2014;P is the linker containing at least one non-alpha amino acid with a cyclic group, at least one substituted bile acid or at least one non-alpha amino acid, and G is the GRP receptor targeting peptide. In the preferred embodiment, M is an Aazta metal chelator or a derivative thereof. Methods for imaging a patient and/or providing radiotherapy or phototherapy to a patient using the compounds of the invention are also provided. Methods and kits for preparing a diagnostic imaging agent from the compound is further provided. Methods and kits for preparing a radiotherapeutic agent are further provided.

Gastrin releasing peptide compounds

Novel methods of treating prostate tumors or of delaying the progression of prostate tumors are also provided, including, methods of treating bone or soft tissue metastases of prostate cancer methods for treating hormone sensitive and hormone refractory prostate cancer, methods for delaying the progression of hormone sensitive prostate cancer, for facilitating combination therapy in patients with hormone sensitive prostate cancer and for decreasing aberrant vascular permeability in patients with hormone sensitive prostate cancer, said methods comprising the step of administering to a subject a dose comprising an amount of radioactively labeled L70, N-[4-[[[[[4,7,10-Tris(carboxymethyl)-1,4,7,10-tetraazacyclododec-1-yl]acetyl]amino]acetyl]amino]benzoyl]-L-glutaminyl-L-tryptophyl-L-alanyl-L-valyl-glycyl-L-histidyl-L-leucyl-L-methioninamide. 

Improved compounds for use in diagnostic imaging or therapy having the formula M-N-O-P-G, wherein M is an optical label or a metal chelator (in the form complexed with a metal radionuclide or not), N-O-P is the linker, and G is the GRP receptor targeting peptide. Methods for imaging a patient and/or providing radiotherapy or phototherapy to a patient using the compounds of the invention are also provided. Methods and kits for preparing a diagnostic imaging agent from the compound are further provided. Methods and kits for preparing a radiotherapeutic agent are further provided.

New and improved compounds for use in radiodiagnostic imaging or radiotherapy having the formula M-N&#x2014;O&#x2014;P-G, wherein M is the metal chelator (in the form complexed with a metal radionuclide or not), N&#x2014;O&#x2014;P is the linker, and G is the GRP receptor targeting peptide. Methods for imaging a patient and/or providing radiotherapy to a patient using the compounds of the invention are also provided. A method for preparing a diagnostic imaging agent from the compound is further provided. A method for preparing a radiotherapeutic agent is further provided.

New and improved compounds for use in diagnostic imaging or therapy having the formula M-N&#x2014;O&#x2014;P-G, wherein M is a metal chelator having the structure: wherein R1-R5 and FG are define herein (in the form complexed with a metal radionuclide or not), N&#x2014;O&#x2014;P is the linker containing at least one non-alpha amino acid with a cyclic group, at least one substituted bile acid or at least one non-alpha amino acid, and G is the GRP receptor targeting peptide. In the preferred embodiment, M is an Aazta metal chelator or a derivative thereof. Methods for imaging a patient and/or providing radiotherapy or phototherapy to a patient using the compounds of the invention are also provided. Methods and kits for preparing a diagnostic imaging agent from the compound is further provided. Methods and kits for preparing a radiotherapeutic agent are further provided.

New and improved compounds for use in diagnostic imaging or therapy having the formula M&#x2014;N&#x2014;O&#x2014;P&#x2014;G, wherein M is an optical label or a metal chelator (in the form complexed with a metal radionuclide or not), N&#x2014;O&#x2014;P is the linker, and G is the GRP receptor targeting peptide. Methods for imaging a patient and/or providing radiotherapy or phototherapy to a patient using the compounds of the invention are also provided. Methods and kits for preparing a diagnostic imaging agent from the compound is further provided. Methods and kits for preparing a radiotherapeutic agent are further provided.

A process for the preparation of (S)-N,N'-bis[2-hydroxy-1-(hydroxymethyl)ethyl]-5-[(2-hydroxy-1-oxo-propyl)amino]-2,4,6-triiodo-1,3-benzendicarboxamide (iopamidol) starting from 5-amino-N,N&#x2032;-bis[2-hydroxy-1-(hydroxymethyl)ethyl]-2,4,6-triiodo-1,3-benzenedicarboxamide (II) which process comprises a) reacting the compound of formula (II) with a suitable protecting agent, to give a compound of formula (III) wherein R is a group of formula A or B wherein Ris a hydrogen atom, a C&#xf7;Cstraight or branched alkoxy group, Ris hydrogen, a C&#xf7;Cstraight or branched alkoy group and R3 ?is a C&#xf7;Cstraight or branched alkyl group, a trifuoromethyl or a trichloromethyl group; b) acylating the amino group in position 5 of the intermediate compound of formula (III), by reaction with a (S)-2-(acetyloxy)propanoyl chloride to give a compound of formula (IV) wherein R is as defined above; and c) removing all the acyl groups present in the compound of formula (IV) under basic conditions, with prior cleavage of the cyclic protections of the hydroxy groups in the carboxamido substituents under acidic conditions, when R is a group of formula A carboxamido hydroxy groups under acidic conditions. The invention also refers to the new intermediates of formula (III) and (IV) wherein &#x2014;R is a group A.

Process for the preparation of iopamidol and the new intermediates therein

The invention relates to a process for the preparation of a compound of formula (I), wherein R represents a 2,3-dihydroxy-1-propyl or a 1,3-dihydroxy-2-propyl radical, via direct amidation of a dialkyl ester of 5-amino-1,3-benzenedicarboxylic acid of formula (V), wherein Rrepresents a straight or branched (C-C)-alkyl group, with at least the stoichiometric amount of an amine of formula HNR.

Process for the preparation of N,N-substituted 5-amino-1,3-benzenedicarboxamides

New and improved compounds for use in radiodiagnostic imaging or radiotherapy having the formula M-N-O-P-G, wherein M is the metal chelator (in the form complexed with a metal radionuclide or not), N-O-P is the linker, and G is the GRP receptor targeting peptide. Methods for imaging a patient and/or providing radiotherapy to a patient using the compounds of the invention are also provided. A method for preparing a diagnostic imaging agent from the compound is further provided. A method for preparing a radiotherapeutic agent is further provided.

A process for the preparation of (S)-N,N'-bis[2-hydroxy-1-(hydroxymethyl)ethyl]-5-[(2-hydroxy-1-oxo-propyl)amino]-2,4,6-triiodo-1,3-benzendicarboxamide (iopamidol) starting from 5-amino-N,N&#x2032;-bis[2-hydroxy-1-(hydroxymethyl)ethyl]-2,4,6-triiodo-1,3-benzenedicarboxamide (II) which process comprises a) reacting the compound of formula (II) with a suitable protecting agent, to give a compound of formula (III) wherein R is a group of formula A or B wherein Ris a hydrogen atom, a C&#xf7;Cstraight or branched alkoxy group, Ris hydrogen, a C&#xf7;Cstraight or branched alkoxy group and R3 ?is a C&#xf7;Cstraight or branched alkyl group, a trifuoromethyl or a trichloromethyl group; b) acylating the amino group in position 5 of the intermediate compound of formula (III), by reaction with a (S)-2-(acetyloxy)propanoyl chloride to give a compound of formula (IV) wherein R is as defined above; and c) removing all the acyl groups present in the compound of formula (IV) under basic conditions, with prior cleavage of the cyclic protections of the hydroxy groups in the carboxamido substituents under acidic conditions, when R is a group of formula A carboxamido hydroxy groups under acidic conditions. The invention also refers to the new intermediates of formula (III) and (IV) wherein &#x2014;R is a group A.

Process for the preparation of iopamidol and the new intermediated therein

Compounds able to chelate paramagnetic metal ions and the use thereof as contrast agents in the technique known as &ldquo;Magnetic Resonance Imaging&rdquo; (M.R.I.).

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Seregno, Italy

Enrico Cappelletti