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Pyrrolobenzodiazepines compound

A technology of compounds and solvates, applied in the field of pyrrolobenzodiazepine dimers

Inactive Publication Date: 2008-04-30
MEDIMMUNE LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0009] The present inventors found that compounds such as ZC-207 had solubility problems which were solved by using different types of these compounds

Method used

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  • Pyrrolobenzodiazepines compound
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  • Pyrrolobenzodiazepines compound

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0267] (a) (2S, 4R)-N-(benzyloxycarbonyl)-2-tert-butyldimethylsilyloxymethyl-4-hydroxypyrrolidine (1)

[0268]

[0269] Starting from trans-4-hydroxy-L-proline, compound 1 was obtained in high yield according to a four-step process known in the art (S.J.Gregson et al., J.Med.Chem., 2004, 1161-1174 ).

[0270] (b) (2S, 4R)-N-(benzyloxycarbonyl-2-vin-butyldimethylsilyloxymethyl-4-oxyacetylpyrrolidine (2)

[0271]

[0272] To stirred 1(76.9g, 211mmol) in anhydrous THF (1L) solution. After stirring the reaction mixture for 16 hours, TLC (95:5 v / v CHCl 3 / MeOH) showed complete consumption of starting material. Excess solvent was removed by rotary evaporation, the residue was dissolved in EtOAc (1 L), washed with 1N HCl (2×1 L), H 2 O (1L), brine (1L), dried (MgSO 4 ). Filtration and evaporation of solvent gave acetate 2 (80.7 g, 94%) as a colorless oil: 1 H NMR (400MHz, CDCl 3 ) (rotamer) δ7.36-7.12 (m, 5H), 5.30-5.10 (m, 3H), 4.09-3.97 (m, 2H), 3.74-3.55 (m, 3H), 2....

Embodiment 2

[0313] (a) 1,1'-[[(propane-1,3-diyl)dioxy]bis[(11S,11aS)-10-(2,2,2-trichloroethoxycarbonyl)- 11-(tert-butyldimethylsilyloxy)-7-methoxy-2-(naphthalen-2-yl)-1,10,11,11a-tetrahydro-5H-pyrrolo[2 , 1-c][1,4]benzodiazepin-5-one]](17)

[0314]

[0315] At room temperature, TEA (0.15mL, 1.05mmol, 6.0eq) in H 2 A solution of O (1 mL) and EtOH (10 mL) was added to a solution of 13 (251 mg, 0.17 mmol) in toluene (6 mL). To this mixture was added 2-naphthylboronic acid (77.9mg, 0.45mmol, 2.6eq) and Pd(PPh 3 ) 4 (8.0 mg, 7 μmol, 0.04 eq). The reaction mixture was heated under microwave irradiation at 100 °C for 20 min, at which time thin layer chromatography (80:20 v / v EtOAc / Hexane) showed complete consumption of starting material. Excess solvent was removed, the residue was dissolved in EtOAc (20 mL), washed with H 2 O (15mL), brine (15mL) washed, dried (MgSO 4 ). Filtration and evaporation of the solvent gave the crude product, which was purified by flash column chromatography...

Embodiment 3

[0323] (a) 1,1'-[[(propane-1,3-diyl)dioxy]bis[(11S,11aS)-10-(2,2,2-trichloroethoxycarbonyl)- 11-(tert-butyldimethylsilyloxy)-7-methoxy-2-(thiophen-2-yl)-1,10,11,11a-tetrahydro-5H-pyrrolo[2 , 1-c][1,4]benzodiazepin-5-one]](20)

[0324]

[0325] The H of TEA (0.11mL, 0.82mmol, 6.0eq) 2 A solution of O (0.8 mL) and EtOH (5 mL) was added to a solution of 13 (197 mg, 0.14 mmol) in toluene (5 mL). To this mixture was added thiophene-2-boronic acid (45.5mg, 0.36mmol, 2.6eq) and Pd(PPh 3 ) 4 (6.3 mg, 5 μmol, 0.04 eq). The reaction mixture was stirred at room temperature for 3 hours at which time thin layer chromatography (80:20 v / v EtOAc / Hexanes) showed complete consumption of starting material. Excess solvent was removed, the residue was dissolved in EtOAc (20 mL), washed with H 2 O (15mL), brine (15mL) washed, dried (MgSO 4 ). Filtration and evaporation of the solvent gave the crude product, which was purified by flash column chromatography (80:20 v / v hexane / EtOAc) to aff...

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Abstract

Compounds of the formula: (I) or solvate thereof, wherein: R<2> is an optionally substituted C5-20 aryl group; R<6> and R<9> are independently selected from H, R, OH, OR, SH, SR, NH2, NHR, NRR', nitro, Me3Sn and halo; where R and R' are independently selected from optionally substituted C1-12 alkyl, C3-20 heterocyclyl and C5-20 aryl groups; R<7> is selected from H, R, OH, OR, SH, SR, NH2, NHR, NHRR', nitro, Me3Sn and halo; R'' is a C3-12 alkylene group, which chain may be interrupted by one or more heteroatoms and / or aromatic rings; X is selected from O, S, or NH; z is 2 or 3; M is a monovalent pharmaceutically acceptable cation; R<2>', R<6>', R<7>', R<9>', X' and M' are selected from the same groups as R<2>, R<6>, R<7>, R<9>, X and M respectively, or M and M' may together represent a divalent pharmaceutically acceptable cation.

Description

technical field [0001] The present invention relates to pyrrolobenzodiazepines (PBDs), especially pyrrolobenzodiazepine dimers bearing C2 aryl substituents. Background technique [0002] Certain pyrrolobenzodiazepines (PBDs) have the ability to recognize and bind to specific DNA sequences; the preferred sequence is PuGPu. The first PBD antitumor antibiotic antramycin was found in 1965 (Leimgruber, et al., J.Am.Chem.Soc., 87, 5793-5795 (1965); Leimgruber, et al., J.Am.Chem.Soc., 87, 5791-5793 (1965)). Since then, many naturally occurring PBDs have been reported, and more than 10 synthetic routes have been developed for various analogs (Thurston, et al., Chem. Rev. 1994, 433-465 (1994)). Members of this family include abbeymycin (Hochlowski, et al., J. Antibiotics, 40, 145-148 (1987)), chicamycin (Konishi, et al., J. Antibiotics, 37, 200-206 (1984)), DC-81 (Japanese Patent 58-180 487; Thurston, et al., Chem. Brit., 26, 767-772 (1990); Bose, et al., Tetrahedron, 48, 751-758 ...

Claims

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Application Information

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IPC IPC(8): C07D519/00A61P35/00A61K31/5517
Inventor S·J·格雷格森P·W·霍华德陈治治
Owner MEDIMMUNE LTD
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