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Inhibitors of carbonic anhydrase IX

A general formula, complex technology, applied in the field of radiolabeled inhibitors

Inactive Publication Date: 2011-06-01
分子洞察制药股份有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0012] Currently, many small molecule inhibitors of CA-IX exhibit undesired side effects due to inhibition of other CA isoenzymes present in target organs

Method used

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  • Inhibitors of carbonic anhydrase IX
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  • Inhibitors of carbonic anhydrase IX

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0390]

[0391] 4-(bis(pyridin-2-ylmethyl)amino)benzenesulfonamide (2a)

[0392]A suspension of sulfonamide (1a, 5.0 g, 29 mmol) and pyridine-2-carbaldehyde (6 mL, 64 mmol) in EtOH (100 mL) was heated to reflux and stirred at room temperature for 30 minutes. The solvent was removed in vacuo to give a yellow solid. The resulting residue was dissolved in EtOH (100 mL), cooled to 0° C., and sodium triacetoxyborohydride (4.4 g, 120 mmol) was added portionwise. The resulting mixture was stirred at 0°C for 1 hour, then allowed to warm to room temperature for 3 hours. 2N sodium hydroxide (25 mL) was carefully added to quench the reaction. The resulting mixture was poured into saturated sodium bicarbonate (200 mL) and extracted with DCM (3×150 mL). Dry (Na2SO4) and concentrate the combined organic extracts. Flash column chromatography as a gradient elution (DCM / MeOH, 1:0 to 9:1), followed by crystallization from ethyl acetate afforded 2a as a white solid (3.41 g, 33%). 1 H NMR...

Embodiment 2

[0410] 4-Oxo-4-(4-sulfamoylphenethylamino)butanoic acid

[0411] Combine 4-(2-aminoethyl)benzenesulfonamide (1 g, 5.0 mmol) and succinic anhydride (500 mg, 5.0 mmol) in a round bottom flask containing dioxane (100 mL) and heat the slurry to reflux overnight. The white solid was filtered and washed with cold dioxane to give the desired product as a white solid (1.4 g, 4.6 mol, 92%). 1 H NMR (400MHz, DMSO-d 6 )δ8.00(s, 1H), 7.71(d, J=8.1Hz, 2H), 7.36(d, J=8.1Hz, 2H), 7.38(s, 1H), 3.26(m, 2H), 2.75( t, J=7.1Hz, 2H), 2.5(m, 2H), 2.3(t, J=7.1Hz, 2H); (M+H) + (301).

[0412]

[0413] Rhenium(I)N tricarbonyl bromide 1 -(4-(bis(pyridin-2-ylmethyl)amino)butyl)-N 4 -(4-sulfamoylphenethyl)succinamide

[0414] 4-Oxo-4-(4-sulfamoylphenethylamino)butanoic acid (210mg, 0.68mmol) and tricarbonylrhenium(I) bromide (N 1 , N 1 - bis(pyridin-2-ylmethyl)propane-1,4-diamine) (404 mg, 1.34 mmol) was dissolved in DMF (2 mL) and DIPEA (1.5 mL). The slurry was stirred at room temperature u...

Embodiment 3

[0417] tert-Butyl 6-(bis(pyridin-2-ylmethyl)amino)hexylcarbamate

[0418]Commercially available BOC-1,6-diaminohexane (5.0 g, 23.5 mmol) was added to DEC (250 mL), and 2-pyridinecarbaldehyde (4.1 mL, 51.7 mmol). The solution was stirred at room temperature for 10 minutes, then sodium triacetoxyborohydride (11.5 g, 54 mmol) was added in one portion. The solution was stirred overnight at room temperature. The bright yellow solution was evaporated to dryness, treated with 2N sodium hydroxide (150 mL) and extracted with DCM (4×150 mL). The organic extract was dried over sodium sulfate and concentrated to give a yellow oil (7.15 g, 76% yield). (M+H) + (399).

[0419]

[0420] Tricarbonylrhenium(I) bromide tert-butyl 6-(bis(pyridin-2-ylmethyl)amino)hexylcarbamate

[0421] In a pressure tube, combine tert-butyl 6-(bis(pyridin-2-ylmethyl)amino)hexylcarbamate (355 mg, 0.89 mmol) into methanol (4 mL) and add Re(CO) 3 (H 2 O) 2 Br (360mg, 0.9mmol), stirred overnight at 125°C ...

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Abstract

Novel radiopharmaceuticals that are useful in diagnostic imaging and therapeutic treatment of disease characterized by over expression of CA-IX comprise a complex that contains a sulfonamide moiety which is capable of binding the active catalytic site of CA- IX, and a radionuclide adapted for radioimaging and / or radiotherapy.

Description

[0001] Cross References to Related Applications [0002] This application claims priority to U.S. Provisional Application No. 61 / 020,043, filed January 9, 2008, U.S. Provisional Application No. 61 / 088,980, filed August 14, 2008, and filed December 31, 2008 Priority to US Provisional Application No. 61 / 142,002, the disclosure of which is hereby incorporated by reference. technical field [0003] The present invention relates generally to radiopharmaceuticals for imaging diagnosis and therapeutic treatment of disease. In particular, the present invention relates to radiolabeled inhibitors of carbonic anhydrase IX (CA-IX). Background technique [0004] The expression of different proteins on the surface of tumor cells offers the opportunity to diagnose and characterize disease by probing phenotypic features, biochemical composition, and tumor activity. Radioactive molecules that selectively bind to specific tumor cell surface proteins enable the use of non-invasive imaging te...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/18A61K31/4192A61K31/444A61K51/04A61P35/00
CPCA61K51/0474A61K31/18A61K31/444A61K51/0453A61K51/0406A61K51/0459A61K51/0455A61K51/0446A61K31/4192A61K31/555C07D285/135C07C311/37C07C335/16C07C335/20C07D403/12C07D401/12C07D417/12C07D249/04C07D213/36A61P35/00A61P43/00
Inventor 克雷格·齐默曼约翰·W·巴比奇约翰·乔亚尔陆根良凯温·P·马雷斯卡克里斯·巴龙
Owner 分子洞察制药股份有限公司
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