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Triazine radiopharmaceuticals and radiocontrast agents

A compound, CH2 technology, used in in vivo radioactive preparations, drug combinations, clinical applications of radiodiagnosis, etc., can solve problems such as low permeability of monoclonal antibodies

Active Publication Date: 2019-03-26
MOLECULAR INSIGHT PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the use of mAbs for diagnosis and tumor detection has been limited by the low penetration of mAbs in solid tumors

Method used

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  • Triazine radiopharmaceuticals and radiocontrast agents
  • Triazine radiopharmaceuticals and radiocontrast agents
  • Triazine radiopharmaceuticals and radiocontrast agents

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0218] Example 1: (2S)-2-(3-((1S)-1-carboxy-5-(8-((4-(dimethylamino)-6-((4-((1,4, 7,10-tetra(carboxymethyl)-1,4,7,10-tetraazacyclododec-2-yl)methyl)phenyl)amino)-1,3,5-triazine-2 -yl)amino)octanoyl)pentyl)ureido)glutaric acid lutetium complex.

[0219]

[0220] Step 1: (18S,22S)-tri-tert-butyl 1-(9H-fluoren-9-yl)-3,12,20-trioxo-2-oxa-4,13,19,21-tetraaza Tetracosane-18,22,24-tricarboxylate.

[0221]

[0222] Stir (S)-di-tert-butyl 2-(3-((S)-6-amino-1-(tert-butoxy)-1-oxohexane-2-yl)ureido)pentanedi Ester (1.9677g, 4.03mmol), 8-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)octanoic acid (1.84g, 4.84mmol), 1-ethyl-3-(3 -Dimethylaminopropyl)carbodiimide) (EDCI; (0.770g, 4.03mmol), HOBt (0.544g, 4.03mmol) and N,N-diisopropylethylamine (DIPEA; (2.0mL) ) in DCE (100 mL) overnight. Evaporation of the solvent gave a residue which was purified by silica gel column chromatography (Biotage) using a mixture of DCM / MeOH as eluent to give a white solid (18S, 22S) -Tri-tert-butyl 1-(9H...

Embodiment 2

[0231] Example 2. (S)-2-(3-((S)-1-carboxy-5-(8-((4-(piperidin-1-yl)-6-((4-((((S )-1,4,7,10-tetra(carboxymethyl)-1,4,7,10-tetraazacyclododecane-2-yl)methyl)phenyl)amino)-1,3, 5-triazin-2-yl)amino)octanoyl)pentyl)ureido)glutaric acid lutetium complex.

[0232]

[0233] Step 1. (2S)-2-(3-((S)-1-carboxy-5-(8-(4-(piperidin-1-yl)-6-(4-((1,4,7 ,10-tetra(carboxymethyl)-1,4,7,10-tetraazacyclododecane-2-yl)methyl)phenylamino)-1,3,5-triazin-2-yl Amino) octanoyl) pentyl) ureido) glutaric acid.

[0234]

[0235] DIPEA (0.10 mL). The reaction mixture was stirred at room temperature for 2 hours, then the solvent was removed using a stream of nitrogen to give a residue. The obtained residue was dissolved in DMSO (4.0 mL) and (S)-di-tert-butyl 2-(3-((S)-6-(8-aminooctanoyl)-1-(tert-butoxy base)-1-oxohexane-2-yl)ureido)glutarate (31.4mg, 0.05mmol) and K 2 CO 3 (100mg). The suspension was stirred at room temperature for 2 hours, then piperidine (0.10 mL) was added. The reaction mi...

Embodiment 3

[0238] Example 3. (2S)-2-(3-((1S)-1-carboxy-5-(8-(4-morpholinyl-6-(4-((1,4,7,10-tetra (Carboxymethyl)-1,4,7,10-tetraazacyclododec-2-yl)methyl)phenylamino)-1,3,5-triazin-2-ylamino)octanoyl ) pentyl) ureido) lutetium glutarate complex.

[0239]

[0240] Step 1. (2S)-2-(3-((1S)-1-carboxy-5-(8-(4-morpholinyl-6-(4-((1,4,7,10-tetra( Carboxymethyl)-1,4,7,10-tetraazacyclododec-2-yl)methyl)phenylamino)-1,3,5-triazin-2-ylamino)octanoyl) Pentyl) ureido) glutaric acid.

[0241]

[0242] DIPEA (0.10 mL). The reaction was stirred at room temperature for 2 hours, then the solvent was removed using a stream of nitrogen to give a residue. The residue was dissolved in DMSO (4.0 mL) and (S)-di-tert-butyl 2-(3-((S)-6-(8-aminooctanoyl)-1-(tert-butoxy )-1-oxohexane-2-yl)ureido)glutarate (31.4mg, 0.05mmol) and K 2 CO 3 (100 mg) was added to the DMSO solution. The suspension was stirred at room temperature for 2 hours, then morpholine (0.10 mL) was added and the reaction mixture was st...

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Abstract

The compounds according to general formula (I) and general formula (II) of the present invention are potent inhibitors of PSMA. The pharmaceutical composition may comprise a complex of a radionuclide and a compound of general formula (I) or a compound of general formula (II). The methods of the present invention involve the use of compounds of general formula (I) or radionuclide complexes of compounds of general formula (II) for the treatment or diagnosis of diseases or conditions associated with PSMA activity.

Description

[0001] Cross References to Related Applications [0002] This application claims the benefit of U.S. Provisional Patent Application No. 61 / 752,350, filed January 14, 2013, and U.S. Provisional Patent Application No. 61 / 785,788, filed March 14, 2013, both U.S. Provisional Patent Applications The entire content of is incorporated herein by reference. technical field [0003] The technology of the present invention relates generally to the field of radiopharmaceuticals and their use as tracers, imaging agents in nuclear medicine and in the treatment of various disease states. Background technique [0004] Many tumors express unique proteins that are indicators of malignancy and poor prognosis. The expression of these proteins on the surface of tumor cells provides a unique opportunity to use these proteins as markers for the diagnosis of cancer conditions to assess the progression of cancer conditions and as delivery targets for radiotherapeutics. Radioactive molecules that ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): A61K51/00
CPCC07D401/14C07D403/14C07D413/14A61K51/0497A61P1/04A61P1/16A61P1/18A61P11/00A61P13/08A61P13/10A61P13/12A61P15/00A61P17/00A61P19/00A61P25/00A61P35/00A61P43/00C07F5/003A61B6/481A61B6/50
Inventor 约翰·W·巴比奇克雷格·齐默曼约翰·乔亚尔陆根良
Owner MOLECULAR INSIGHT PHARMA