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a technology of compounds and compounds, applied in the field of compounds, can solve the problems of unsuitability of techniques, less compatible with the range of possible c, and higher yield of

Inactive Publication Date: 2004-10-07
SPIROGEN
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Exposure of E to hydrazine / Raney nickel avoids the production of tin salts and may result in a higher yield of C, although this method is less compatible with the range of possible C and A-ring substituents.
For instance, if there is C-ring unsaturation (either in the ring itself, or in R.sub.2 or R.sub.3), this technique may be unsuitable.

Method used

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Examples

Experimental program
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Effect test

example 2

Synthesis of Resin-bound 7,8-Dimethoxy PBD (12) (FIG. 2)

[0116] Attaching Dimethoxy A-Ring to form Resin (10)

[0117] Dichloromethane CH.sub.2Cl.sub.2 (2 mL) was added to the choloroformate resin 2 (0.05 mmol) (prepared as in Example 1) and the vessel allowed to shake for 30 minutes. The suspension was cooled to 0.degree. C., a solution of 4,5-dimethoxyanthranilic acid 9 (0.05 g, 0.25 mmol) and pyridine (20 .mu.L) in NMP (2 mL) added, and the vessel allowed to shake at room temperature for 16 hours. The resin 10 was collected by filtration, and then rinsed with CH.sub.2Cl.sub.2 (2.times.5 mL), NMP (2.times.5 mL) and MeOH (2.times.5 mL). The entire procedure was repeated twice and the resin was then dried in vacuo. IR (reflectance, cm.sup.-1): 1750-1650 (CONH).

[0118] Attaching Pyrrolo C-Ring to form Resin (11)

[0119] Dimethyl formamide DMF (5 mL) was added to resin 10 (0.05 mmol) and the vessel allowed to shake for 30 minutes. Pyrrolidine methanol 5 (0.025 g, 0.25 mmol), TBTU (0.08 g, 0....

example 3

Alternative Synthesis of Resin-bound 7,8-Dimethoxy PBD (21) (FIGS. 3 & 4)

[0122] Overall Synthetic Strategy

[0123] The on-bead oxidation step employed in the previous approaches can be avoided by coupling an anthranilic acid loaded resin to the dimethyl acetal 16 derived from proline (FIG. 4). In this approach, unmasking of the dimethyl acetal protected aldehyde leads to spontaneous B-ring closure. Thus, exposure of the acetal 20 to a palladium catalyst (Pd(CH.sub.3CN).sub.2Cl.sub.2) leads to the formation of the cyclized compound 21. The acetal 20 was derived from the anthranilic acid resin 19 and the acetal 16, which were coupled together under standard conditions. The acetal 16 was obtained from the Cbz protected compound 15 (FIG. 3) by hydrogenation; i5 was in turn prepared by acetalisation of the aldehyde 14. Swern oxidation of the primary alcohol 13 afforded the aldehyde 14, the primary alcohol was prepared by a lithium tetrahydroborate reduction of the commercially available Cb...

example 4

Further Alternative Synthesis of 7,8-Dimethoxy PBD (13) (FIG. 5)

[0139] Overall Synthetic Strategy

[0140] This synthesis used the on-bead oxidation step of example 1 and 2 to obtain the resin-bound PBD 34, but using the Dess Martin reagent and Swern oxidation. The resin used to bind the required anthranilic acid 31 is p-nitrophenyl carbonate Wang resin, which can directly couple the anthranilic acid without the need for interactive transformation to the chloroformate and thus eliminating a process step.

[0141] Synthesis Route

[0142] A suspension of p-nitrophenyl carbamate Wang resin 31 (1 g, 0.93 mmol / g loading) in CH.sub.2Cl.sub.2 / DMF (2:1, 10 mL) was shaken for 30 minutes. A solution of dimethoxyanthranilic acid 9 (0.92 g, 4.7 mmol), HOBt (0.37 g, 2.8 mmol) and DIPEA (0.97 mL, 5.5 mmol) in CH.sub.2Cl.sub.2 / DMF (2:1, 20 mL) was added to the swollen resin. The vessel was allowed to shake at room temperature for 6 hours. Resin 32 was filtered and rinsed with DMF (2.times.10 mL), CH.sub.2...

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Abstract

A compound of formula (I), wherein: R2 and R3 are independently selected from H, R, OH, OR, =O, =CH-R, =CH2, CH2-CO2R, CH2-CO2H, CH2-SO2R, O-SO2R, CO2R, COR and CN, and there is optionally a double bond between C1 and C2 or C2 and C3; R6, R7, R8 and R9 are independently selected from H, R, OH, OR, halo, nitro, amino, Me3Sn; R11 is either H or R; Q is S, O or NH; L is a linking group, or a single bond; O is a solid support; or where one or more of R2, R3, R6, R7 and R8 are independently: H-(T)n-X-Y-A- where: X is CO, NH, S or O; T is a combinatorial unit; Y is a divalent group such that HY=R; A is O, S, NH, or a single bond and n is a positive integer.

Description

[0001] This invention relates to pyrrolobenzodiazepines, to methods of synthesizing these compounds on solid supports, and to collections of these compounds. This invention further relates to methods for identifying and isolating pyrrolobenzodiazepine compounds with useful and diverse activities from such collections.BACKGROUND TO THE INVENTION[0002] Compounds having biological activity can be identified by screening diverse collections of compounds (i.e. libraries of compounds) produced through synthetic chemical techniques. Such screening methods include methods wherein the library comprises a plurality of compounds synthesized at specific locations on the surface of a solid support whereby a receptor is appropriately labelled to bind to and identify a compound, e.g., fluorescent or radioactive labels. Correlation of the labelled receptor bound to the support and its location ox the support identifies the binding compound (U.S. Pat. No. 5,143,854).[0003] Central to these methods i...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K31/5517A61P31/00A61P43/00C07D487/04
CPCC07D487/04A61P31/00A61P43/00
Inventor THURSTON, DAVID EDWINHOWARD, PHILIP WILSON
Owner SPIROGEN
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