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Probes for imaging huntingtin protein

An imaging agent, pharmaceutical salt technology, used in the field of probes for imaging huntingtin protein

Active Publication Date: 2018-06-08
CHDI FOUND
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

There are at least two major challenges in designing clinical trials for pre-HD: selecting participants who are most likely to show measurable changes over the course of the clinical trial, and developing intervention-sensitive interventions that can show differences in the natural history of pre-HD. outcome measure

Method used

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  • Probes for imaging huntingtin protein
  • Probes for imaging huntingtin protein
  • Probes for imaging huntingtin protein

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0476] Example 1, Method 1: 10-Methoxy-N-(pyridin-3-yl)-7-thia-2,5-diazatricyclo[6.4.0.0 2 ,6 ]Dodeca-1(12),3,5,8,10-pentaene-4-carboxamide

[0477] 1 H NMR (500MHz, DMSO) 10.47(s, 1H), 9.04(d, J=2.3Hz, 1H), 8.98(s, 1H), 8.34-8.23(m, 2H), 8.11(d, J=8.9Hz , 1H), 7.73 (d, J=2.5Hz, 1H), 7.47-7.30 (m, 1H), 7.19 (dd, J=8.9, 2.5Hz, 1H), 3.84 (s, 3H). Tr(MET-uHPLC-AB-101)=1.92min, m / z(ES + )(M+H) + 325.

[0478] The following examples were prepared using Method 1 as described above or its analogues.

[0479] Table 1

[0480]

[0481]

[0482]

[0483]

[0484]

[0485] Method 2

[0486] Solution for Method 2

[0487]

[0488] Step 1, Method 2: 10-Hydroxy-7-thia-2,5-diazatricyclo[6.4.0.0 2,6 ]Dodeca-1(8),3,9,11-tetraene-4-carboxylic acid

[0489] 10-methoxy-7-thia-2,5-diazatricyclo[6.4.0.0 2,6 ] Dodeca-1(8),3,9,11-tetraene-4-carboxylic acid (638 mg, 2.57 mmol, prepared by Method 1) was suspended in dichloromethane (50 mL) and stirred for five minutes. 1 ...

Embodiment 1

[0492] Example 1, Method 2: 10-Hydroxy-N-(6-methoxypyridin-3-yl)-7-thia-2,5-diazatricyclo[6.4.0.0 2,6 ]Dodeca-1(8),3,9,11-tetraene-4-carboxamide

[0493] 1 H NMR (500MHz, DMSO) 10.22(s, 1H), 10.08(s, 1H), 8.85(s, 1H), 8.61(d, J=2.6Hz, 1H), 8.15(dd, J=8.9, 2.7Hz ,1H),7.97(d,J=8.8Hz,1H),7.41(d,J=2.3Hz,1H),6.97(dd,J=8.7,2.4Hz,1H),6.82(d,J=8.9Hz ,1H), 3.83(s,3H). Tr(MET-uHPLC-AB-101)=2.48min, m / z(ES + )(M+H) + 341,94%.

[0494] The following examples were prepared using Method 2 as described above:

[0495] Table 2

[0496]

[0497]

[0498] Method 3

[0499] Solution for method 3

[0500]

[0501] Step 1, Method 3: 1,8,10-Triazatricyclo[7.4.0.0 2,7 ]Trideca-2(7),3,5,8,10,12-hexaene-11-carboxylic acid ethyl ester

[0502] 1H-benzimidazol-2-amine (2g, 15.02mmol) and (3E)-4-(dimethylamino)-2-oxobut-3-enoic acid ethyl ester (70%, 4g, 16.36mmol , described in US2011001121) was suspended in acetic acid (50 mL) and the reaction mixture was heated at 120 °C for 16 h....

Embodiment 1

[0507] Example 1, Method 3: N-(6-methoxypyridin-3-yl)-1,8,10-triazatricyclo[7.4.0.0 2,7 ]Trideca-2(7),3,5,8,10,12-hexaene-11-carboxamide

[0508] 1 H NMR (500MHz, DMSO) 11.06(s, 1H), 9.77(d, J=7.0Hz, 1H), 8.71(d, J=2.6Hz, 1H), 8.43(d, J=8.2Hz, 1H), 8.22(dd, J=8.9,2.7Hz,1H),7.96(d,J=8.2Hz,1H),7.77(d,J=7.0Hz,1H),7.64(appt t,J=7.7Hz,1H) , 7.53 (appt t, J = 7.7Hz, 1H), 6.89 (d, J = 8.9Hz, 1H), 3.87 (s, 3H). Tr(MET-uHPLC-AB-101)=2.19min, m / z(ES + )(M+H) + 320.

[0509] The following examples were prepared using method 3 as described above:

[0510] table 3

[0511]

[0512]

[0513]

[0514]

[0515] Method 4

[0516] Solution for method 4

[0517]

[0518] Step 1, Method 4: 10-Methoxy-N-[6-(methylcarbamoyl)pyridin-3-yl]-7-thia-2,5-diazatricyclo[6.4.0.0 2,6 ]Dodeca-1(12),3,5,8,10-pentaene-4-carboxamide

[0519] 10-Methoxy-7-thia-2,5-diazatricyclo[6.4.0.0 in pyridine (2 mL) 2,6 ] dodeca-1(12), 3,5,8,10-pentaene-4-carboxylic acid (95%, 100 mg, 0.38 mmol, de...

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Abstract

Provided are imaging agents comprising a compound of Formula I, or a pharmaceutically acceptable salt thereof, and methods of their use.

Description

[0001] Cross References to Related Applications [0002] This application claims priority under 35 U.S.C. §119(e) to U.S. Provisional Application 62 / 211,118, filed August 28, 2015, which is hereby incorporated by reference in its entirety. technical field [0003] The present application relates to an abnormal imaging agent that binds to HTT protein with high sensitivity and specificity for molecular imaging and a method of using the imaging agent. Background technique [0004] The advent of molecular imaging methods such as positron emission tomography (PET) and single photon emission computed tomography (SPECT) has enabled the measurement of molecular and cellular mechanisms throughout the body in preclinical and clinical settings. Such measurements have broad diagnostic utility and their use to assess response to therapy and to aid in drug development is rapidly developing. Many experts cite the recent introduction of high-resolution molecular imaging technology as a maj...

Claims

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Application Information

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IPC IPC(8): A01N43/42
CPCA61K51/0459C07B59/002A61K51/0455C07D513/04C07D487/04C07D513/14C07B2200/05
Inventor C·多明格斯J·维特雅克J·巴德C·J·布朗M·E·普莱姆P·D·约翰逊T·M·克鲁尔D·克拉克-弗鲁D·希金斯M·R·米尔斯R·W·马斯顿S·科S·L·J·格林S·海耶斯
Owner CHDI FOUND
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