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Library of compounds labelled with radioisotope

A radioactive isotope and compound technology, applied in the direction of organic compound library, chemical library, organic compound preparation, etc., can solve the problems of prolonging time and increasing cost

Inactive Publication Date: 2006-03-29
XCELERON LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] With the AMS approach, however, radiolabeled candidate compounds must be provided after initial selection by conventional methods, which requires synthesis of radiolabeled drug candidates to order
While microdosing means that only tiny amounts of drug need to be synthesized, the need for to-order synthesis and scale-up is the bottleneck for this method of choice, adding significantly to cost and time

Method used

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  • Library of compounds labelled with radioisotope
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  • Library of compounds labelled with radioisotope

Examples

Experimental program
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Effect test

Embodiment 1

[0129] Example 1 - Incorporation of traces into the ring 14 C Synthesis of Labeled Benzoic Acid Liquid / Solid Phase Libraries

[0130] Typical examples of chemical library products are described in the Ugi reaction (Cao, X., Moran, EJ., Siev, D., Lio, A., Ohashi, C and Mjalli, AMM; 1995., Boorg and Med Chem Lett., 5: 2953-2958; and Nakamura, M., Inoue, J and Yamada, T., 2000., Bioorg and Med Chem Lett., 10: 2807-2810) This reaction can be carried out in liquid or on immobilized resin, including Condensation of 4 reactants, in this case carboxylic acids, amines, aldehydes and isocyanides. The final product (ie, library compound) will vary depending on the different reactants chosen.

[0131] The following are some exploratory experiments using the mixture of reactants as described in Table 1. Reactions x1-x9 are carried out in liquid. Reactions x21-x29 were performed with TentaGel S-RAM resin. This solid support can donate amino groups for use in the reaction.

[0132]...

Embodiment 1Bx4---x4

[0142] The synthesis of embodiment 1Bx4---x4

[0143] Using the general procedure for 1B above, benzylamine (44ml, 0.4mmol) and cyclopentanecarbaldehyde (48[mu]l, 0.4mmol) were added to anhydrous methanol (0.5ml). The resulting solution was stirred at 28°C for 10 minutes. To this solution was added anhydrous methanol (1ml) 14 C Slightly labeled benzoic acid (from 1A) (48 mg, 0.4 mmol) followed by cyclohexylisocyanide (0.4 mmol). The reaction was stirred at 28°C for 60 hours, and the resulting crude precipitate was filtered, washed with ice-cold methyl alcohol, and dried in vacuo to obtain crude N-benzyl-N-(cyclohexylcyclohexylcarbamoylmethyl)benzamide (122mg, 71%)

[0144] 1 H NMR□ □ (400MHz, CDCl 3 )7.55-6.85(m, 10H), 4.67(d, J 16.2Hz, 1H), 4.45(d, J 16.2Hz, 1H), 4.17(d, J 9.5Hz, 1H), 3.66(m, 1H), 2.41 (m, 1H), 1.95-1.45(m, 10H), 1.40-0.85(m, 10H).

[0145] 13 C NMR □c (400MHz, CDCl 3 )24.6, 25.5, 25.7, 25.7, 26.3, 29.7, 30.2, 32.6, 32.9, 36.1, 47.7, 52.9, 66.7, 126...

Embodiment 1Cx22---x22

[0149] The synthesis of embodiment 1Cx22---x22

[0150] Using the general procedure for 1C above, Rink resin ((1.1 mmol, 0.055 g) was deprotected with 20% piperidine in dichloromethane (DCM) (3 x 1 ml). The resin was dissolved in 50% DCM:MeOH (1 ml) Swell in the medium for 30 minutes. Add valeraldehyde (64 μl, 10 equivalents, according to the initial resin loading) to the pre-swelled resin, and stir the reaction mixture for 10 minutes at 28° C. Add 14 C Mildly labeled benzoic acid (from 1A) (73 mg, 10 equiv) and cyclohexylisocyanide (76 μl, 10 equiv), the resin was stirred at 28°C for 36 hours. The resin was washed with DCM (10 x 5ml) and dried in vacuo. The resin was cleaved with 30% TFA:DCM (1 ml) for 3 hours. The resin was removed by filtration, and the filtrate was concentrated under reduced pressure to obtain crude N-(1-cyclohexylcarbamoylpentyl)benzamide (17.9 mg, 94%).

[0151] 1 H NMR□ □ (400MHz, CDCI 3 ) 7.82 (d, J 7Hz, 2H), 7.54-7.42 (m, 3H), 6.61 (d, J8Hz, 1H)...

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Abstract

Library of compounds or their pharmaceutically acceptable salts, each compound being associated with information on its chemical identity and structure, wherein at least two of the compounds is labelled with radioisotope characterised in that the radioisotope is an AMS active radioisotope; a solid support having a compound or its pharmaceutically acceptable salt as hereindefined bound thereto, the compound being associated with information on its chemical identity and structure and comprising a radioisotope, characterised in that the radioisotope is an AMS active radioisotope as hereinbefore defined; process for the preparation of a library of compounds as claimed in any of Claims 1 to 19 comprising radioisotope labelling a plurality of compounds, each compound being associated with information on its chemical identity and structure characterised in that labelling is with an AMS active radioisotope; a kit therefor; Method for selecting one or more candidate compounds comprising screening a library of the invention comprising AMS active radioisotope labelled compounds as hereinbefore defined and obtaining a sample from the screen or submitting a compound identified for metabolic studies and obtaining a sample therefrom, and performing, AMS detection of the sample; and use of the library, a solid support comprising radioisotope labelled compound or a method as hereinbefore defined in (bio)medical, agrochemical, environmental and like screening for further study by AMS detection.

Description

technical field [0001] The present invention relates to a library of radioisotope-labeled compounds for the detection of individual compounds, methods of preparing the library, methods of selecting from the library candidate compounds having desired characteristics and testing them in simultaneous or subsequent studies, and the library Use in compound selection and detection; more specifically, the present invention relates to a library of compounds labeled with radioactive isotopes of AMS (accelerator mass spectrometry) activity for the detection of individual compounds, a method for preparing the library, and selection from the library with Candidate compounds of desired characteristics and methods of detecting them with AMS, and the use of the library in compound selection, especially drug screening; and AMS detection providing in vivo metabolic characteristics of compounds. Background technique [0002] The drug discovery and development process in the pharmaceutical and...

Claims

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Application Information

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IPC IPC(8): G01N33/58G01N33/68C07B61/00G01N33/60
CPCC40B40/04C07C237/22C07C2101/08C07C2101/14C07B2200/05G01N33/60C07D295/13C07C2601/08C07C2601/14C40B20/08C40B70/00
Inventor R·C·加纳G·J·拉平
Owner XCELERON LTD
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