WO2000021982A1 - Procede de preparation d'un agent d'imagerie de thrombus - Google Patents

Procede de preparation d'un agent d'imagerie de thrombus Download PDF

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Publication number
WO2000021982A1
WO2000021982A1 PCT/US1999/021628 US9921628W WO0021982A1 WO 2000021982 A1 WO2000021982 A1 WO 2000021982A1 US 9921628 W US9921628 W US 9921628W WO 0021982 A1 WO0021982 A1 WO 0021982A1
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Prior art keywords
compound
formula
salt form
contacting
xii
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PCT/US1999/021628
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English (en)
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John Bishop
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Du Pont Pharmaceuticals Company
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Priority to AU63938/99A priority Critical patent/AU6393899A/en
Priority to EP99951511A priority patent/EP1121378A1/fr
Priority to JP2000575887A priority patent/JP2002527451A/ja
Priority to CA002341975A priority patent/CA2341975A1/fr
Publication of WO2000021982A1 publication Critical patent/WO2000021982A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/08—Tripeptides
    • C07K5/0802—Tripeptides with the first amino acid being neutral
    • C07K5/0804—Tripeptides with the first amino acid being neutral and aliphatic
    • C07K5/0808—Tripeptides with the first amino acid being neutral and aliphatic the side chain containing 2 to 4 carbon atoms, e.g. Val, Ile, Leu
    • 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
    • A61K51/082—Peptides, e.g. proteins, carriers being peptides, polyamino acids, proteins the peptide being a RGD-containing 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
    • 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
    • C07C271/22—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 carboxyl groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
    • C07K7/50—Cyclic peptides containing at least one abnormal peptide link
    • C07K7/54—Cyclic peptides containing at least one abnormal peptide link with at least one abnormal peptide link in the ring
    • C07K7/56—Cyclic peptides containing at least one abnormal peptide link with at least one abnormal peptide link in the ring the cyclisation not occurring through 2,4-diamino-butanoic acid

Definitions

  • the present invention relates generally to an efficient and practical commercial synthesis of novel reagents for the preparation of radiopharmaceuticals useful as imaging agents for the diagnosis of cardiovascular disorders, infection, inflammation and cancer, and to intermediate compounds useful for the preparation of these reagents .
  • These reagents are comprised of stable hydrazine-modified biologically active molecules that react with gamma emitting radioisotopes to form radiopharmaceuticals that selectively localize at sites of disease, allowing an image to be obtained of the loci using gamma scintigraphy .
  • Radiopharmaceuticals comprised of gamma-ray emitting radionuclide labeled biologically active molecules fulfill this need.
  • the biologically active molecules serve to localize the radionuclides at the sites of disease and thus allow the sites to be visualized by gamma scintigraphy.
  • the molecules are generally proteins, antibodies, antibody fragments, peptides, polypeptides, or peptidomimetics .
  • the molecules interact with a receptor or binding site expressed at the sites of the disease or with a receptor or binding site on an endogenous blood component, such as platelets and leukocytes, that accumulates at the sites.
  • This interaction results in selective localization of a percentage of the injected radiopharmaceutical while the remainder is cleared either through the renal or hepatobiliary systems.
  • the localized radiopharmaceutical is then imaged externally using gamma scintigraphy.
  • a number of radiopharmaceuticals comprised of radionuclide labeled proteins, antibodies or antibody fragments are under development.
  • hydrazines and hydrazides as chelators to modify proteins for labeling with radionuclides has been disclosed by Schwartz et . al . in U.S. Patent 5,206,370.
  • the protein is modified by reaction with bifunctional aromatic hydrazines or hydrazides having a protein reactive substituent.
  • the hydrazino-modified protein is reacted with a reduced technetium species, formed by reacting pertechnetate with a reducing agent in the presence of a chelating dioxygen ligand.
  • the technetium becomes bound to the protein through what are believed to be hydrazido or diazenido linkages with the coordination sphere completed by the ancillary dioxygen ligands .
  • U.S. Patent 5,750,088 indicates the value of the compound of formula (I) as a novel reagent for the described imaging agents.
  • a viable chemical synthesis which permits its commercial manufacture is therefore desirable.
  • the present invention describes a convergent process for the preparation of (I) which reduces production time through the consolidation of several key chemical transformations. The process described herein supresses the formation of undesired side-products, thus maximizing product purity.
  • the present invention provides an environmentally favorable alternative to the use of reactions and purification protocols which employ the use of carcinogenic and other hazardous solvents .
  • the present invention relates generally to processes for the efficient production of (I) which has been acheived by the inventors' discovery that a compound of formula (I), which is an important precursor to radiopharmaceuticals useful as imaging agents , and intermediate compounds useful for the preparation of these reagents, may be formed by high yielding and commercially viable processes described herein.
  • the present invention provides a novel process for the preparation of a compound of formula (I) :
  • cyclizing comprises contacting the compound of formula (XV) with a cyclizing agent in a cyclizing solvent, in the presence of a second base;
  • deprotecting comprises contacting the compound of formula (XVI) with strong acid at a suitable temperature;
  • desalting comprises dissolving the compound of formula (XVIII) in an aqueous base solution, followed by adjusting the pH of the solution to give a compound of formula (I) .
  • the cyclizing agent is O- (lH-benzotriazol-1-yl) -N,N,N' ,N' -tetramethyluronium tetraflouroborate;
  • the cyclizing solvent is acetonitrile
  • the second base is N,N-diisopropylethylamine
  • the strong acid is a mixture of trifluoroacetic acid and trifluoromethanesulfonic acid;
  • the suitable temperature is from about -30 °C to about 5 °C;
  • the compound of formula (XVII) is its di (trifluoromethanesulfonic acid) salt form
  • the first base is N,N-diisopropylethylamine
  • the quenching agent is ammonium acetate
  • the aqueous base solution comprises sodium hydroxide in water
  • adjusting the pH comprises the addition of aqueous hydrochloric acid to the solution until a pH in the range of about 4.1 to about 4.4 is achieved.
  • the compound of formula (XVI) is purified using a C-18 column by loading about 369 g of the reaction solution from step 11 per L of bed volume .
  • the compound of formula (XVIII) is purified using a C-18 column by loading about 33 g of the reaction product from step 13i per L of bed volume.
  • the compound of formula (XV) is prepared by a process comprising:
  • coupling comprises contacting the compound of formula (VI) with the compound of formula (XIII) in the presence of a coupling agent and a third base;
  • deprotecting comprises hydrogenating the compound of formula (XIV) under suitable hydrogen pressure in the presence of a hydrogenation catalyst in a hydrogenation solvent.
  • the compound of formula (VI) is in its trifluoroacetic acid salt form
  • the coupling agent is 0- (lH-benzotriazol-1-yl) -
  • the third base is N,N-diisopropylethylamine
  • the suitable pressure is about 14.7 psi
  • the hydrogenation catalyst is palladium on carbon; and, the hydrogenation solvent is methanol .
  • the compound of formula (IX) is prepared by the process comprising:
  • the polar aprotic solvent is N,N-dimethylformamide
  • the second coupling agent is N,N' -dicyclohexylcarbodiimide.
  • the present invention provides a novel process for preparation of a compound of formula (VI) :
  • the compound of formula (VI) is its trifluoroacetic acid salt form
  • the coupling agent is O- (lH-benzotriazol-1-yl) -
  • the base is N,N-diisopropylethylamine
  • deprotecting comprises contacting the compound of formula
  • the compound of formula (V) is its hydrochloric acid salt form.
  • the compound of formula (V) is prepared by the process comprising:
  • the compound of formula (IV-a) is its p-toluenesulfonic acid salt form
  • the second coupling agent is 0- (lH-benzotriazol-1-yl) - N,N,N' ,N' -tetramethyluronium hexaflourophosphate;
  • the second base is N,N-diisopropylethylamine
  • deprotecting comprises contacting the compound of formula (V-b) with hydrochloric acid at a temperature in the range of about -20 °C to about 0 °C; and, the compound of formula (V) is its hydrochloric acid salt form.
  • the present invention provides a novel process for the preparation of a compound of formula
  • the compound of formula (XII) is its di (hydrochloric acid) salt
  • the compound of formula (XII-b) is its sodium salt form.
  • the compound of formula (XII) is prepared by the process comprising:
  • the suitable temperature is in the range of about 100 °C to about 125 °C;
  • the compound of formula (XII) is the di (hydrochloric acid) salt
  • reducing comprises hydrogenating the compound of formula
  • the compound of formula (III) is prepared by the process comprising:
  • the coupling agent is 1- (3-dimethylamino propyl) -3-ethylcarbodiimide and the coupling is performed in acetonitrile and at a temperature in the range of about -10 °C to about 10 °C.
  • the compound of formula (XII-b) is prepared by the process comprising:
  • Ts or "tosyl” as used herein means a 4-methylphenylsulfonyl protecting group
  • Boc as used herein means a butyloxycarbonyl protecting group
  • DMF as used herein means N,N- dimethylformamide
  • THF as used herein means tetrahydrofuran
  • EtOAc as used herein means ethyl acetate
  • MTBE as used herein means methyl t-butyl ether
  • TFA as used herein means trifluoroacetic acid
  • TFMSA as used herein means trifluoromethanesulfonic acid
  • OSu as used herein means N-hydroxysuccinimido
  • RT as used herein means room temperature
  • psi as used herein means pounds per square inch
  • HPLC as used herein means high performance liquid chromatography
  • suitable solvents which may be readily selected by one of skill in the art of organic synthesis, said suitable solvents generally being any solvent which is substantially nonreactive with the starting materials (reactants) , the intermediates, or products at the temperatures at which the reactions are carried out, i.e., temperatures which may range from the solvent's freezing temperature to the solvent's boiling temperature.
  • a given reaction may be carried out in one solvent or a mixture of more than one solvent.
  • suitable solvents for a particular reaction step may be selected.
  • suitable solvents may include, by way of example and without limitation, chlorinated solvents, hydrocarbon solvents, ether solvents, polar protic solvents and polar aprotic solvents.
  • Suitable halogenated solvents include, but are not limited to carbon tetrachloride, bromodichloromethane, dibromochloromethane, bromoform, chloroform, bromochloromethane, dibromomethane, butyl chloride, dichloromethane, tetrachloroethylene, trichloroethylene, 1, 1, 1-trichloroethane, 1, 1, 2-trichloroethane, 1,1- dichloroethane, 2-chloropropane, hexafluorobenzene, 1, 2, 4-trichlorobenzene, o-dichlorobenzene, chlorobenzene, fluorobenzene , fluorotrichloromethane, chlorotrifluoromethane, bromotrifluoromethane, carbon tetrafluoride, dichlorofluoromethane, chlorodifluoromethane, trifluoromethane, 1, 2-dichlorotetrafluor
  • Suitable hydrocarbon solvents include, but are not limited to benzene, cyclohexane, pentane, hexane, toluene, cycloheptane, methylcyclohexane, heptane, ethylbenzene, m-, o-, or p-xylene, octane, indane, nonane, chlorobenzene, or naphthalene .
  • Suitable ether solvents include, but are not limited to dimethoxymethane, tetrahydrofuran, 1,3-dioxane, 1,4-dioxane, furan, diethyl ether, ethylene glycol dimethyl ether, ethylene glycol diethyl ether, diethylene glycol dimethyl ether, diethylene glycol diethyl ether, triethylene glycol dimethyl ether, anisole, or t-butyl methyl ether.
  • Suitable polar protic solvents include, but are not limited to methanol, ethanol, 2-nitroethanol, 2- fluoroethanol, 2 , 2 , 2-trifluoroethanol, ethylene glycol, 1- propanol, 2-propanol, 2-methoxyethanol, 1-butanol, 2- butanol, i-butyl alcohol, t-butyl alcohol, 2-ethoxyethanol, diethylene glycol, 1-, 2-, or 3- pentanol, neo-pentyl alcohol, t-pentyl alcohol, diethylene glycol monomethyl ether, diethylene glycol monoethyl ether, cyclohexanol, benzyl alcohol, phenol, and glycerol .
  • Suitable polar aprotic solvents include, but are not limited to dimethylformamide (DMF) , dimethylacetamide (DMAC) , 1, 3-dimethyl-3 , 4, 5, 6-tetrahydro-2 (1H) -pyrimidinone (DMPU) , 1,3 -dimethyl-2-imidazolidinone (DMI), N-methylpyrrolidinone (NMP) , formamide, N-methylacetamide, N-methylformamide, acetonitrile, dimethylsulfoxide, propionitrile, ethyl formate, methyl acetate, hexachloroacetone, acetone, ethyl methyl ketone, ethyl acetate, isopropyl acetate, t-butyl acetate, sulfolane, N,N- dimethylpropionamide, nitromethane, nitrobenzene, hexamethylphosphoramide .
  • DMF dimethylformamide
  • coupling solvent refers to any solvent in which an amine may be reacted with an carboxylic acid derivative to form an amide.
  • Examples of such coupling solvents include, but are not limited to ether, halogenated, hydrocarbon, and polar aprotic solvents.
  • strong acid includes, but is not limited to mineral acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, lithium bisulfate, potassium bisulfate, sodium bisulfate, and ammonium chloride; and organic acids such as formic acid, acetic acid, trifluoroacetic acid, trifluoromethanesulfonic acid, ethanoic acid, propionic acid, butyric acid, valeric acid and caproic acid.
  • mineral acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, lithium bisulfate, potassium bisulfate, sodium bisulfate, and ammonium chloride
  • organic acids such as formic acid, acetic acid, trifluoroacetic acid, trifluoromethanesulfonic acid, ethanoic acid, propionic acid, butyric acid, valeric acid and caproic acid.
  • suitable base includes any of a variety of bases, the presence of which in a reaction facilitates the synthesis of the desired product.
  • Suitable bases may be selected by one of skill in the art of organic synthesis.
  • Suitable bases include, but are not limited to, inorganic bases such as alkali metal, alkali earth metal, thallium, and ammonium hydroxides, alkoxides, phosphates, and carbonates, such as sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, thallium hydroxide, thallium carbonate, tetra-n- butylammonium carbonate, and ammonium hydroxide.
  • Suitable bases also include organic bases, including but not limited to aromatic and aliphatic amines, such as pyridine; trialkyl amines such as triethylamine, N,N-diisopropylethylamine, N,N-diethylcyclohexylamine, N,N-dimethylcyclohexylamine, N,N,N' -triethylenediamine, N,N-dimethyloctylamine; 1, 5-diazabicyclo[4.3.0] non-5-ene (DBN) ; 1, 4-diazabicyclo[2.2.2] octane (DABCO) ; 1, 8-diazabicyclo[5.4.0 ]undec-7-ene (DBU) ; tetramethylethylenediamine (TMEDA) ; substituted pyridines such as N,N-dimethylaminopyridine (DMAP) ,
  • DMAP tetramethylethylenediamine
  • aqueous base includes, but is not limited to lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, lithium bicarbonate, sodium bicarbonate and potassium bicarbonate.
  • aqueous base solution includes, but is not limited to aqueous systems in which aqueous bases are dissolved, which may or may not include additional organic solvent constituents .
  • An example of an aqueous base solution includes, but is not limited to, sodium hydroxide in water.
  • Coupled agents refers to any agent known in the art of organic synthesis or peptide chemistry, which is capable of facilitating the formation of an amide bond from a carboxylic acid and an amine .
  • examples of such agents include, but are not limited to dicyclohexyl- carbodiimide (DCC) , diisopropylcarbodiimide (DIC) , carbonyldiimidazole (CDI) , 1- (3-dimethylaminopropyl) -3- ethylcarbodiimide (EDC) , 0- (lH-benzotriazol-1-yl) -N,N,N' ,N' - tetramethyluronium tetraflouroborate (TBTU) , and benzotriazol-1-yl-oxy-tripyrrolidinophosphonium hexafluorophosphate (PyBOP) , (benzotriazolyloxy) tris (dimethyl
  • cyclizing agent includes any agent with is capable of facilitating the formation of an intramolecular amide bond from a carboxylic acid and an amine.
  • examples of such agents include, but are not limited to those named herein as coupling agents.
  • suitable pressures range from atmospheric to any pressure obtainable in a laboratory or industrial plant.
  • hydrogenation catalysts are those which facilitate the removal of a protecting group known in the art of organic synthesis to be labile to hydrogen. These catalysts are also those which are known in the art to reduce a nitro group to an amino group and a cyano group to an aminomethyl group.
  • Such hydrogenation catalysts include, but are not limited to palladium on carbon, palladium hydroxide on carbon, palladium on calcium carbonate poisoned with lead, platinum on carbon, and platinum (IV) oxide.
  • hydrogenation solvents are those solvents known in the art of organic synthesis to be useful solvents for reactions which occur under a hydrogen atmosphere, such as hydrogenations . Examples of such solvents include, but are not limited to polar protic solvents such as methanol, ethanol, propanol, isopropanol and the like, ethers, and hydrocarbons, etc.
  • the compounds described herein may have asymmetric centers. Unless otherwise indicated, all chiral, diastereomeric and racemic forms are included in the present invention. It will be appreciated that compounds of the present invention that contain asymmetrically substituted carbon atoms may be isolated in optically active or racemic forms . Methods on how to prepare optically active forms from optically active starting materials are known in the art, such as by resolution of racemic forms or by synthesis. All chiral, diastereomeric, racemic forms and all geometric isomeric forms of a structure are intended.
  • the present invention includes all isotopes of atoms occurring in the intermediates or final compounds.
  • Isotopes include those atoms having the same atomic number but different mass numbers.
  • isotopes of hydrogen include tritium and deuterium; isotopes of carbon include 13 C and 14 C.
  • counterion refers either a negative or positive ion, which serves as a pairing partner in the salts of the intermediates or products described. Examples of counterions include, but are not limited to, ammonium, trifluoroacetate, chloride, and sodium.
  • pharmaceutically acceptable salts refer to derivatives of the disclosed compounds wherein the intermediates or final compound are modified by making acid or base salts of the intermediates or final compounds. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like.
  • compounds of the present invention contain a variety of ionic centers. Thus, depending on the pH of the solution, it is likely that more than one ion will be present in some of the compounds of the present invention (i.e., zwitterions) . As a result, both external and internal salts are considered to be part of the present invention.
  • the pharmaceutically acceptable salts of the intermediates or final compounds include the conventional non-toxic salts or the quaternary ammonium salts from non- toxic inorganic or organic acids.
  • such conventional non-toxic salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like; and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2- acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic, and the like.
  • the pharmaceutically acceptable salts are generally prepared by reacting the free base or acid with stoichiometric amounts or with an excess of the desired salt-forming inorganic or organic acid or base in a suitable solvent or various combinations of solvents.
  • the pharmaceutically acceptable salts of the acids of the intermediates or final compounds are prepared by combination with an appropriate amount of a base, such as an alkali or alkaline earth metal hydroxide e.g. sodium, potassium, lithium, calcium, or magnesium, or an organic base such as an amine, e.g., dibenzylethylenediamine, trimethylamine, piperidine, pyrrolidine, benzylamine and the like, or a quaternary ammonium hydroxide such as tetramethylammoinum hydroxide and the like.
  • a base such as an alkali or alkaline earth metal hydroxide e.g. sodium, potassium, lithium, calcium, or magnesium
  • an organic base such as an amine, e.g., dibenzylethylenediamine, trimethylamine, piperidine, pyrrolidine, benzylamine and the like, or a quaternary ammonium hydroxide such as tetramethylammoinum hydroxide and the like.
  • pharmaceutically acceptable salts of the compounds of the invention can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid, respectively, in water or in an organic solvent, or in a mixture of the two; generally, nonaqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred. Lists of suitable salts are found in Remington's Pharmaceutical Sciences, 17th ed. , Mack Publishing Company, Easton, PA, 1985, p. 1418, the disclosure of which is hereby incorporated by reference.
  • Multigram scale is preferably the scale wherein at least one starting material is present in 10 grams or more, more preferably at least 50 grams or more, even more preferably at least 100 grams or more.
  • Multikilogram scale is intended to mean the scale wherein more than one kilogram of at least one starting material is used.
  • Industrial scale as used herein is intended to mean a scale which is other than a laboratory scale and which is sufficient to supply product sufficient for either clinical tests or distribution to consumers.
  • the compound of formula (III) can be prepared by contacting a compound of formula (II) with a first coupling agent.
  • the first coupling agent is preferably l-(3- dimethylaminopropyl) -3-ethylcarbodiimide.
  • the coupling reaction is preferably run in a polar aprotic solvent (e.g, CH 3 CN) and at a temperature in the range of about -10 °C to about 10 °C.
  • Step 2 By contacting a compound of formula (IV) with a compound of formula (IV-a) or a salt form thereof (e.g., the p-toluenesulfonic acid salt) in the presence of a second coupling agent and a second base, a compound of formula (IV- b) is prepared.
  • the second coupling agent is O- (lH-benzotriazol-1-yl) -N,N,N' ,N' -tetramethyluronium hexaflourophosphate and the second base is N,N- diisopropylethylamine.
  • (IV-b) may be isolated. This intermediate may also then be purified.
  • the compound of formula V or a salt form thereof (e.g, the hydrochloric acid salt) can then be arrived at by deprotection of (IV-b) .
  • Deprotection can be performed by contacting the compound of formula (V-b) with a strong acid (e.g., hydrochloric acid) at a temperature in the range of about -20 °C to about 0 °C.
  • a strong acid e.g., hydrochloric acid
  • Step 3 By contacting a compound of formula (V) or a salt form thereof (e.g., the HC1 salt) with a compound of formula (V-a) in the presence of a coupling agent and a base, one can prepare a compound of formula (V-b) .
  • the coupling agent is preferably O- (lH-benzotriazol-1-yl) -N,N, N' , N' - tetramethyluronium hexaf1ourophosphate and the base is preferably N,N-diisopropylethylamine .
  • in situ intermediate (V-b) may be isolated and may also then be purified.
  • Step 3-i Deprotecting the compound of formula (V-b) results in a compound of formula (VI) , or a salt form thereof (e.g., the trifluoroacetic acid salt).
  • Deprotecting comprises contacting the compound of formula (V-b) with a strong acid (e.g., trifluoroacetic acid), preferably at a temperature in the range of about -20 °C to about 0 °C.
  • a strong acid e.g., trifluoroacetic acid
  • Step 4 The compound of formula (VIII) can be formed by contacting a compound of formula (VII) with hydrazine.
  • Step 5 Contacting the compound of formula (VIII) with a compound of formula (VHI-a) and N-hydroxysuccinimide in a polar aprotic solvent in the presence of a second coupling agent provides a compound of formula (IX) .
  • the polar aprotic solvent is preferably DMF
  • the second coupling agent is preferably DCC.
  • the compound of formula (XI) can be prepared by contacting a compound of formula (X) with thionyl chloride, tetramethylene sulfone, and sulfamide.
  • thionyl chloride Preferably at least one mole equivalent of each of thionyl chloride, tetramethylene sulfone, and sulfamide are used.
  • Even more preferably, 1.6 eq. of thionyl chloride, 9.2 eq. of sulfolane and 1.2 eq. of sulfamide are used.
  • a suitable temperature is in the range of about 100 °C to about 125 °C;
  • Step 7 Reducing the compound of formula (XI) provides a compound of formula (XII), or a salt form thereof (e.g., the di-HCl salt form) .
  • Reducing preferably involves hydrogenating the compound of formula (XI) under hydrogen pressure of about 50 psi to about 70 psi, in the presence of a hydrogenation catalyst (e.g., platinum (IV) oxide).
  • Step 8 Saponifying a compound of formula (XII) or a salt form (e.g., the di-HCl salt form) thereof and contacting the resulting compound with a compound of formula (Xll-a) yields a compound of formula (XII-b) or a salt form thereof (e.g., the Na salt) .
  • Saponification includes contacting a compound of formula (XII) or a salt form thereof with an aqeuous base solution (e.g., NaOH/H 2 ⁇ ) and adjusting the aqueous base solution to an appropriate pH.
  • the appropriate pH is preferably in the range of about 7.5 to about 8.5, more preferably 7.9-8.1, and the adjustment is preferably made using a strong acid such as HCl .
  • the compound of formula XII-b can then be manipulated to a compound of formula XIII via Step 8-i.
  • Step 8a As an alternative to step 8, instead of saponifying a compound of formula (XII) , a compound of formula (XII-c) , or a salt form (e.g., the di-HCl salt form) thereof, can be contacted with a base (e.g., NaOH) and the resulting product contacted with a compound of formula (XII- a) to yield a compound of formula (XII-b) or a salt form thereof (e.g., the Na salt).
  • a base e.g., NaOH
  • Step 8-i Contacting the compound of formula (XII-b) with a compound of formula (III) affords the compound of formula (XIII), or a salt form thereof.
  • the contacting is performed at a temperature in the range of about 0-5 «C.
  • Step 9 Coupling of a compound of formula (VI) or a salt form thereof (e.g., a TFA salt) with a compound of formula (XIII) or a salt form thereof renders a compound of formula (XIV) .
  • Coupling in this step is intended to include contacting the two compounds in the presence of a coupling agent and a third base.
  • the coupling agent is 0- (lH-benzotriazol-1-yl) -N,N,N' ,N' -tetramethyluronium hexaflourophosphate and the third base is N,N- diisopropylethylamine .
  • Step 10 Deprotecting the compound of formula (XIV) yields the compound of formula (XV), or a salt form thereof.
  • Deprotection in this step includes hydrogenating the compound of formula (XIV) under suitable hydrogen pressure (e.g., about 14.7 psi) in the presence of a suitable hydrogenation catalyst (e.g., Pd/C) in a suitable hydrogenation solvent (e.g., MeOH) .
  • suitable hydrogenation catalyst e.g., Pd/C
  • a suitable hydrogenation solvent e.g., MeOH
  • pressures from atmosphere to 60 psi can be used.
  • Step 11 The compound of formula (XVI) can be prepared by cyclizing a compound of formula (XV) .
  • cyclizing includes contacting the compound of formula (XV) with a cyclizing agent (e.g., 0- (lH-benzotriazol-1-yl) - N,N,N' ,N' -tetramethyluronium tetraflouroborate) in a cyclizing solvent (e.g., CH 3 CN) , in the presence of a second base (e.g., N,N-diisopropylethylamine) .
  • a cyclizing solvent e.g., CH 3 CN
  • the cyclizing solvent is a mixture of CH 3 CN and THF.
  • Step 11 is preferably performed by reverse addition.
  • reverse addition is preferably conducted by adding a solution of the compound of formula (XV) (e.g., XV in CH 3 CN) to a solution of cyclizing agent, cyclizing solvent and second base. More preferably the solution containing the compound of formula (XV) also contains the second base. Even more preferably, the cyclizing agent is dissolved in CH 3 CN and THF.
  • the solution containing the cyclizing agent is heated to a temperature of from 50-70 «C prior to addition of the solution containing a compound of formula (XV) . Even more preferably, the solution containing the cyclizing agent is heated to a temperature of from 57-63 »C prior to addition of XV.
  • the compound of formula (XVI) may be purified using via column chromatography, preferably a C-18 column (e.g., Shandon Hyperprep HS C-18 (12 ⁇ ) column (10 x 55.5 cm)). It is preferred that about 300-400 g, more preferably about 369 g, of reaction mixture per L of bed volume is loaded onto the column. Even though such a large amount of material is loaded onto the column, one can obtain purified material using an appropriate eluent and gradient. Preferably, about 65% water/35% acetonitrile is used with a gradient that brings the mixture to about 42% water/58% acetonitrile over about 120 min. Though the flow rate will affect how quickly the compound of formula (XVI) elutes, at 430 mL/min, one can expect elution when the solvent composition is from about 40-55% acetonitrile.
  • a C-18 column e.g., Shandon Hyperprep HS C-18 (12 ⁇ ) column (10 x 55.5 cm
  • Step 12 Deprotecting the compound of formula (XVI) affords a compound of formula (XVII) or a salt form thereof (e.g., the di (trifluoromethanesulfonic acid) salt).
  • This step is preferably performed by contacting the compound of formula (XVI) with strong acid at a suitable temperature.
  • a preferred strong acid is a mixture of trifluoroacetic acid and trifluoromethanesulfonic acid. This acid mixture is preferably in a ratio of about 1 molar equivalent of TFA to about 4 molar equivalents of TFMSA.
  • a preferred suitable temperature is from about -30-5 °C.
  • Step 13 The compound of formula (XVIII), or an alternative salt form thereof, can be prepared by contacting a compound of formula (XVII) with a compound of formula (IX) in the presence of a first base followed by quenching (Step 13 -i) .
  • the first base is N,N-diisopropylethylamine .
  • the compound of formula (IX) can be other than a sodium salt (e.g., potassium).
  • Step 13 is completed by contacting the compound of formula (XVIII) with a quenching agent.
  • the quenching agent is ammonium acetate.
  • the compound of formula (XVIII) may be purified using via column chromatography, preferably a C-18 column (e.g., Shandon Hyperprep HS C-18 (12 ⁇ ) column (10 x 55.5 cm)). It is preferred that about 30-40 g, more preferably about 33 g, of reaction product per L of bed volume is loaded onto the column. Even though such a large amount of material is loaded onto the column, one can obtain purified material using an appropriate eluent and gradient.
  • the gradient conditions are, start: 10% acetonitrile/90% 50 mM aqueous sodium acetate, end: 17% acetonitrile/83% 50 mM aqueous sodium acetate over about 35 min.
  • a second gradient to achieve 25% acetonitrile/75% 50 mM aqueous sodium acetate over about 260 min.
  • the flow rate will affect how quickly the compound of formula (XVI) elutes, at 450 mL/min, one can expect elution when the solvent composition is from about 19 to 21% acetonitrile.
  • Step 14 Desalting the compound of formula (XVIII) gives the compound of formula (I) .
  • desalting comprises dissolving the compound of formula (XVIII) in an aqueous base solution (e.g., NaOH/H 2 ⁇ ) , followed by adjusting the pH of the solution to give a compound of formula (I) .
  • the pH adjustment of the solution comprises the addition of a strong aqueous acid (e.g., HCI/H 2 O) to the solution until a desired pH is achieved, preferably in the range of about 4.1 to about 4.4.
  • a strong aqueous acid e.g., HCI/H 2 O
  • Boc-6-aminohexanoic acid (II; 1553 g) is dissolved in acetonitrile (13,663 g) and then cooled to 0-4 °C.
  • Ethyl-3- (3-dimethyamino)propylcarbodiimide hydrochloride (EDC; 786 g) is added and the solution is stirred for 3 h at 0-5 °C.
  • EDC Ethyl-3- (3-dimethyamino)propylcarbodiimide hydrochloride
  • the oil is redissolved in ethyl acetate (14,934 g) and water (8,392 g) , and then partitioned.
  • the organic phase is washed two more times with water (8,392 g each), two times with sodium bicarbonate solution (each wash prepared by adding 772 g of sodium bicarbonate to 8,124 g of water), and one time with brine (prepared by adding 2,652 g of sodium chloride to 7,386 g of water).
  • the organic layer is dried over magnesium sulfate (235 g) for 15-30 min, filtered, and then concentrated by rotary evaporation (bath temperature 20-30 °C) .
  • the residue is slurried in cyclohexane (3,525 g) for 60-90 min at 20-25 °C.
  • a reaction vessel is charged sequentially with ethyl acetate (2,805 g) , (IV; 850 g) , (IV-a as the tosylate salt; 765 g) , 2- (lJf-benzotriazol-1-yl) -1, 1, 3 , 3 -tetramethyluronium hexafluorophosphate (HBTU; 850 g) , and more ethyl acetate (1,131 g) .
  • N, N-diisopropylethyl amine (DIEA; 757 g) is added dropwise, maintaining a temperature of 20-30 °C.
  • methyl t-butyl ether (MTBE; 4,956 g) is added while maintaining a temperature of -10--15 °C. After addition is complete, the slurry is warmed to -6-0 °C. Solids are isolated by either filtration or centrifugation and then washed with additional MTBE (1 x 2,508 g and 1 x 5,908 g) . Solids are reslurried in MTBE (6,800 g) for 12-15 h at 20-25 °C and then once again filtered or centrifuged, washing with MTBE (2,465 g) . Vacuum-oven drying (30 °C) affords 1082 g (107 %) of (V) as the hydrochloride salt.
  • MTBE methyl t-butyl ether
  • a reaction vessel is charged sequentially with (V) as the hydrochloride salt (1,077 g) , (V-a) (641 g) , HBTU (1,118 g) , and ethyl acetate (8,190 g) .
  • DIEA is added at a rate such that the temperature remains 20-30 °C.
  • the mixture is then stirred until the reaction is complete by analytical HPLC (typically 18-20 h) .
  • a solution of citric acid (645 g) in water (5,251 g) is added, followed by additional ethyl acetate (205 g) .
  • a second reaction vessel is charged with trifluoroacetic acid (2,436 g) and cooled to • -15 °C.
  • a portion of the (V-b) solution from above (1,295 g) is further diluted with ethyl acetate (160 g) and then added to the reaction vessel at a rate such that the temperature remains -15--10 °C.
  • the addition funnel is rinsed with ethyl acetate (60 g) and the solution is stirred at -7--3 °C until completion by analytical HPLC (typically 22-62 h) .
  • a separate reaction vessel is charged with MTBE (9,322 g) and cooled to 0-5 °C.
  • the reaction mixture from above is added to the MTBE-vessel over the course of 50-70 min. After rinsing with additional MTBE (266 g) , the mixture is stirred for 30-60 min at 0-5 °C, after which solids are collected by filtration or centrifugation. The solids are washed once with MTBE (5,412 g) and once with a mixture of MTBE in cyclohexane (1,623 g each) , and are then slurried in a mixture of MTBE and cyclohexane (5,520 g each) for 2-4 h at 20-25 °C.
  • Solids are washed with MTBE (1,411 g) and then reslurried in methanol (6,997 g) at 70-75 °C (external) for 50-70 min. After a hot filtration, solids are washed with methanol (3,058 g) and MTBE (882 g) , and then dried in a vacuum oven at 87-93 °C until a volatile impurity at 3.2 ppm is no longer visible by X H NMR spectroscopy to afford 639 g (76 %) of (IX) .
  • reaction vessel is charged with (X) (904 g) , sulfamide (463 g) , sulfolane (4,416 g) , and thionyl chloride (1,194 g) , and then heated to 115-122 °C for 14-22 h.
  • the mixture is cooled to 50-60 °C and an additional aliquot of thionyl chloride (177 g) is added, followed by reheating to 115-122 °C for 5-8 h.
  • reaction mixture is worked-up in two portions as follows : A portion of the reaction solution (2,874 g) is added to a flask containing water (16,260 g) while maintaining a temperature of 15-25 °C. After addition is complete, the solution is stirred for 2-3 h at 15-25 °C and solids are either filtered or centrifuged off, rinsing the solids with additional water (2,710 g) . A total of 771 g of crude product is thus obtained. Crude product (770 g) is dissolved in ethyl acetate (19,423 g) by heating to reflux (external temperature 85-95 °C) and then cooling to 55-65 °C.
  • the solution is filtered through Hyflo Super-Cel or Celite (77 g) which is then washed with ethyl acetate (511 g) .
  • the filtrate is concentrated by rotary evaporation (bath temperature »60 °C) and the resulting residue is slurried in ethanol (475 g) and reconcentrated.
  • the ethanol slurry/concentration process is repeated one more time before suspending the solids in ethanol (19,109 g) and heating to 74-78 °C for 12-18 h.
  • the hot solution is filtered through Hyflo Super-Cel or Celite (110 g) which is then washed with ethanol (511 g) .
  • the filtrate is partially concentrated (target weight 10,230 g; additional ethanol may be added if necessary) , brought to reflux (external temperature 85-95 °C) for 30 min, and then cooled to 0-5 °C. After 2-3 h, solids are isolated by filtration or centrifugation and washed with ethanol (730 g) to afford 591 g (71 %) of (XI) .
  • a hydrogenation vessel is charged with (XI) (587 g) , 1- propanol (25,629 g) , and concentrated hydrochloric acid (701 g) .
  • a slurry of platinum (IV) oxide (29 g) in 1-propanol (949 g) is added and the mixture is hydrogenated at approximately 60 psi and 55-60 °C.
  • water 5,695 g
  • the mixture is cooled to 25-35 °C for 30-60 min. Filtration through either a halar filter or Celite affords a filtrate which is concentrated by rotary evaporation (bath temperature • 45 °C) .
  • the residue is slurried in methanol (1,898 g) for approximately 10 min and then reconcentrated. This slurry/concentration process with methanol is repeated one more time before adding a mixture of acetonitrile (5,430 g) and methanol (664 g) and heating to reflux (external temperature 75-85 °C) for 2-3 h. After cooling to 20-25 °C, the mixture is stirred for an additional 2-3 h, and solids are isolated by either filtration or centrifugation.
  • Compound (XII) as the dihydrochloride salt (305 g) is saponified by adding a solution of sodium hydroxide pellets (204 g) in water (1,649 g) at • 30 °C . After addition is complete, the mixture is stirred for 60-80 min and then a solution of concentrated hydrochloric acid (284 g) in water (767 g) is added at 18-22 °C until the pH is 7.9-8.1. The reaction vessel is then charged with (Xll-a) (493 g) and acetonitrile (4,144 g) . The pH is periodically adjusted to 7.9-8.1 by the addition of sodium hydroxide solution (prepared by dissolving 120 g of sodium hydroxide pellets in 1084 g of water) .
  • the aqueous layer is removed and the organic phase is washed three times with water (1,245 g each) and twice with brine (each wash is prepared by adding 588 g of sodium chloride to 1,641 g of water).
  • the organic solution is then dried over magnesium sulfate (169 g) for 15-30 min and filtered (washing with 530 g of ethyl acetate) .
  • the filtrate is concentrated by rotary evaporation (bath temperature 25-35 °C) to afford (XII-b) , redissolved in THF (458 g) , and reconcentrated (bath temperature 25-35 °C) .
  • the THF addition/concentration process is repeated one more time and the residue is then redissolved in a larger quantity of THF (2,590 g) and cooled to 0-3 °C.
  • the resulting oil is redissolved in a larger volume of ethyl acetate (8,301 g) and then washed twice with sodium bicarbonate (once by preparing a solution of 623 g of sodium bicarbonate in 6,493 g of water and once by preparing a solution of 311 g of sodium bicarbonate in 3,246 g of water), once with hydrochloric acid solution (prepared by dissolving 129 g of concentrated hydrochloric acid in 6,394 g of water), and once with brine (prepared by adding 1017 g of sodium chloride to 2,837 g of water) .
  • sodium bicarbonate once by preparing a solution of 623 g of sodium bicarbonate in 6,493 g of water and once by preparing a solution of 311 g of sodium bicarbonate in 3,246 g of water
  • hydrochloric acid solution prepared by dissolving 129 g of concentrated hydrochloric acid in 6,394 g of water
  • brine prepared by adding 1017 g
  • the organic phase is dried over magnesium sulfate (163 g) for 15-30 min, filtered, solids are rinsed with ethyl acetate (667 g) , and the filtrate is partially concentrated (target weight 4,471 g) by rotary evaporation (bath temperature 30- 40 °C) .
  • the solution is cooled to 20-25 °C for 16-20 h, after which solids are filtered or centrifuged off and washed with ethyl acetate (697 g) .
  • Solids are suspended in a mixture of ethyl acetate (504 g) and n-heptane (7,412 g) , and heated to 40-46 °C for 40-60 min. After cooling to 20- 25 °C, solids are isolated by filtration and washed with additional n-heptane . After drying in a vacuum oven (25 °C) , 530 g (65 %) of (XIII) is obtained.
  • a reaction vessel is charged with acetonitrile (3,191 g) , HBTU (325 g) , (XIII) (510 g) , (VI) (602 g) , and additional acetonitrile (287 g) .
  • DIEA (443 g) is added such that the temperature remains at 20-30 °C.
  • the reaction is stirred at 20-25 °C for 6-20 h and monitored by analytical HPLC. If necessary, an additional aliquot of VI (30 g) may be added.
  • Ethyl acetate (6,516 g) is added, followed by a solution of citric acid (530 g of citric acid in 4,774 g of water) .
  • the aqueous phase is separated off, and the organic phase is washed two additonal times with citric acid solution, two times with sodium bicarbonate solution (each wash is prepared by adding 473 g of sodium bicarbonate to 4,935 g of water), and two times with brine (each wash is prepared by adding 1,613 g of sodium chloride to 4,507 g of water) .
  • a flask is charged with acetonitrile (1,744 g) , DIEA (498 g) , (XV) (1,744 g) , and additional acetonitrile (302 g) .
  • a second reaction vessel is charged with HBTU (741 g) and acetonitrile (4,773 g) , and stirred at 15-25 °C until everything is in solution.
  • THF (1,006 g) is added and the mixture is heated to 57-63 °C, after which the (XV) solution from above is added over the course of 1.5-2.5 h.
  • the addition funnel is rinsed with a solution of DIEA (60 g) and acetonitrile (273 g) , and the reaction mixture is stirred for 0.5-5 h and monitored by analytical HPLC. After reaction is complete, the solution is cooled to 15-25 °C (and may be stored for up to 3 weeks at • -5°C) . Portions are removed for preparative HPLC purification .
  • Acetonitrile (13,962 g) is mixed with water (33,150 g) . This mixture is added to a warmed (external temperature 35 °C) portion of the reaction mixture from above (1,625 g) with stirring over 15-30 min. After stirring for 30-90 min at 22-28 °C, the solution is filtered, and the filtrate is purified by preparative HPLC as follows:
  • a Shandon Hyperprep HS C-18 (12 ⁇ ) column (10 x 55.5 cm) is equilibrated with 65 % water/35 % acetonitrile.
  • the solution from above is pumped onto the column.
  • the column is eluded at 430 mL/min under isocratic conditions (65 % water/35 % acetonitrile) for 21 min. This is followed by a linear gradient (to 42 % water/58 % acetonitrile) over 120 min.
  • the main peak typically elutes when the solvent composition is between 40- 55% acetonitrile.
  • the main peak is fractionated and fractions are analyzed by analytical HPLC.
  • a reaction vessel is charged with trifluoroacetic acid (1,258 g) and cooled to 12-18 °C.
  • (XVI) 340 g
  • trifluoromethanesulfonic acid 2,883 g
  • anisole 274 g
  • the mixture is stirred at -5--15 °C until completion by analytical HPLC, and then cooled to -30—25 °C.
  • the reaction is quenched by adding diisopropyl ether (9,860 g) at a rate such that the temperature remains • -25 °C. After addition is complete, the mixture is brought to -25--15 °C. Solids are isolated by either filtration or centrifugation, washed with cool (-15--5 °C) diisopropyl ether (2,465 g) , and then slurried for 5-15 min with diisopropyl ether (4,930 g) at 0-20 °C. Solids are isolated by either filtration or centrifugation, and washed with diisopropyl ether (1,849 g) . The slurry/filtration/wash sequence is repeated one more time, and the resulting solids are dried in a vacuum oven (25 °C) affording 381 g (113 %) of (XVII) as the bis (TFMSA) salt .
  • reaction vessel is charged with (XVII) as the bis (TFMSA) salt (798 g) , (IX) (414 g) , and DMF (13,694 g) .
  • the mixture is stirred at 15-30 °C until all solids are in solution.
  • DIEA (363 g) is then added over 5-20 min, while maintaining the temperature at 15-30 °C, and stirring is continued at 15-30 °C for 16-26 h.
  • ammonium acetate 160 g
  • the mixture is concentrated by rotary evaporation (bath temperature 35-45 °C) .
  • Crude (XVIII) is purified in portions by preparative HPLC.
  • a sample solution is prepared by dissolving crude (XVIII) (147 g) in a solution of 0.1 M aqueous ammonium acetate (4,910 g) and acetonitrile (3,838 g) . After diluting with additional 0.1 M ammonium acetate (40,250 g) , the solution is loaded onto a Shandon Hyperprep HS C-18 (12 ⁇ ) column (10 x 55.5 cm), previously equilibrated with 90 % 50 mM ammonium acetate/10 % acetonitrile. After loading is complete, the material is eluted under linear gradient conditions at 450 mL/min.
  • the gradient conditions are: start: 10% acetonitrile/90% 50 mM aqueous sodium acetate, end: 17% acetonitrile/83% 50 mM aqueous sodium acetate over 35 min.
  • a second gradient is then used to achieve 25% acetonitrile/75% 50 mM aqueous sodium acetate over 260 min.
  • the main peak typically elutes when the solvent composition is between 19-21% acetonitrile.
  • the main peak is fractionated and the resulting fractions may be stored under refrigeration ( ⁇ 15 °C) for up to two weeks.
  • a reaction vessel is charged with acetonitrile (1,153 g) and a solution of sodium hydroxide pellets (8.4 g) dissolved in water (12,105 g) .
  • (XVIII) as the ammonium salt (525 g) is added in portions over 15-45 min at 15-30 °C.
  • the pH is the brought to 6.1-6.5 by the addition of a sodium hydroxide solution (prepared by dissolving 16 g of sodium hydroxide pellets in water, 315g, 1.3M) and stirred until all solids are in solution.
  • Concentrated hydrochloric acid (301 g) is dissolved in water (902 g) and is added portionwise to the the reaction solution at 15-30 °C to bring the pH to 4.1-4.4.

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Abstract

Cette invention se rapporte, de façon générale, à la synthèse de réactifs utiles dans la préparation de produits radiopharmaceutiques qui servent d'agents d'imagerie dans le diagnostic des troubles cardiovasculaires, des infections, des inflammations et du cancer. Ces réactifs sont représentés par la formule (I). Un procédé de préparation d'intermédiaires pertinents est également revendiqué.
PCT/US1999/021628 1998-10-13 1999-10-13 Procede de preparation d'un agent d'imagerie de thrombus WO2000021982A1 (fr)

Priority Applications (4)

Application Number Priority Date Filing Date Title
AU63938/99A AU6393899A (en) 1998-10-13 1999-10-13 A process for the preparation of a thrombus imaging agent
EP99951511A EP1121378A1 (fr) 1998-10-13 1999-10-13 Procede de preparation d'un agent d'imagerie de thrombus
JP2000575887A JP2002527451A (ja) 1998-10-13 1999-10-13 血栓撮像剤の製造方法
CA002341975A CA2341975A1 (fr) 1998-10-13 1999-10-13 Procede de preparation d'un agent d'imagerie de thrombus

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US10392198P 1998-10-13 1998-10-13
US60/103,921 1998-10-13

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WO2000021982A1 true WO2000021982A1 (fr) 2000-04-20

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PCT/US1999/021628 WO2000021982A1 (fr) 1998-10-13 1999-10-13 Procede de preparation d'un agent d'imagerie de thrombus

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EP (1) EP1121378A1 (fr)
JP (1) JP2002527451A (fr)
AU (1) AU6393899A (fr)
CA (1) CA2341975A1 (fr)
HR (1) HRP990317A2 (fr)
TR (1) TR200101039T2 (fr)
WO (1) WO2000021982A1 (fr)

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1996040637A1 (fr) * 1995-06-07 1996-12-19 The Du Pont Merck Pharmaceutical Company Reactifs stables destines a la preparation de produits radiopharmaceutiques

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5750088A (en) * 1993-03-30 1998-05-12 The Dupont Merck Pharmaceutical Company Stable hydrazones linked to a peptide moiety as reagents for the preparation of radiopharmaceuticals
WO1996040637A1 (fr) * 1995-06-07 1996-12-19 The Du Pont Merck Pharmaceutical Company Reactifs stables destines a la preparation de produits radiopharmaceutiques

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
T D HARRIS ET AL.: "Synthesis for the stable hydrazones of a hydrazinonicotinoyl-modified peptide for the preparation of 99mTc-labeled radiopharmaceuticals", BIOCONJUGATE CHEMISTRY., vol. 10, no. 5, 1999, AMERICAN CHEMICAL SOCIETY, WASHINGTON., US, pages 808 - 814, XP002130815, ISSN: 1043-1802 *

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HRP990317A2 (en) 2000-06-30
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EP1121378A1 (fr) 2001-08-08
CA2341975A1 (fr) 2000-04-20

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