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Combinational therapy involving a small molecule inhibitor of the MDM2: p53 interaction

A technology of MDM2 and small molecule compounds, which is applied in the field of treatment of cancer or other proliferative diseases, and can solve problems such as uncertainty of small molecule inhibitors

Inactive Publication Date: 2006-11-01
ORTHO MCNEIL PHARM INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0015] Although combination therapy effects have been demonstrated by various gene therapies that increase gene expression of p53 and decrease gene expression of mdm2, it remains uncertain whether small molecule inhibitors of the HDM2:p53 interaction would be equally effective in such combination therapy

Method used

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  • Combinational therapy involving a small molecule inhibitor of the MDM2: p53 interaction
  • Combinational therapy involving a small molecule inhibitor of the MDM2: p53 interaction
  • Combinational therapy involving a small molecule inhibitor of the MDM2: p53 interaction

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0233] 5-{(3S-3-(4-chlorophenyl)-4-[(R)-1-(4-chlorophenyl)-ethyl]-7-iodo-2,5-dioxo-2 , 3,4,5-Tetrahydrobenzo[e][1,4]diazepin-1-yl}-pentanoic acid

[0234]

[0235] a) 5-{(3S)-3-(4-chlorophenyl)-4-[(R)-1-(4-chlorophenyl)-ethyl]-7-iodo-2,5-diox Substituent-2,3,4,5-tetrahydrobenzo[e][1,4]diazepin-1-yl}-tert-butyl pentanoate

[0236] The title compound was synthesized following the general procedure for the conventional synthesis of diazepines, followed by the general procedure for alkylation of diazepines at the 1 position: Mass Spectrum (LCMS, ESI pos.): C 32 h 33 Cl 2 IN 2 o 4 Calculated for: 706.09; found 707.1 (M+H).

[0237] b) 5-{(3S)-3-(4-chlorophenyl)-4-[(R)-1-(4-chlorophenyl)-ethyl]-7-iodo-2,5-diox Substituent-2,3,4,5-tetrahydrobenzo[e][1,4]diazepin-1-yl}-pentanoic acid

[0238] 5-{(3S)-3-(4-chloro-phenyl)-4-[(R)-1-(4-chloro-phenyl)-ethyl]-7-iodo-2,5-di Oxo-2,3,4,5-tetrahydrobenzo[e][1,4]diazepin-1-yl}-tert-butyl pentanoate (1.0g, 1.4mmol) was dissolved in 20...

Embodiment 2

[0240] 5-{(3S)-3-(4-chlorophenyl)-4-[(R)-1-(4-chlorophenyl)-ethyl]-7-ethynyl-2,5-dioxo -2,3,4,5-Tetrahydrobenzo[e][1,4]diazepin-1-yl}-pentanoic acid

[0241]

[0242] 1 H NMR (400MHz, DMSO-d 6 )δ7.60(d, J=8.6Hz, 2H), 7.53(d, J=2.1Hz, 1H), 7.42-7.33(m, 3H), 7.12(d, J=8.6Hz, 1H), 6.99( d, J=8.4Hz, 2H), 6.57(d, J=7.7Hz, 2H), 6.23-6.15(m, 1H), 5.29(s, 1H), 4.31-4.22(m, 2H), 3.78-3.68 (m, 1H), 2.20-2.12(m, 2H), 1.63(d, J=7.0Hz, 3H), 1.41-1.38(m, 2H), 1.27-1.22(m, 2H). Mass Spectrum (LCMS, ESI pos.): C 30 h 26 Cl 2 N 2 o 4 Calculated for: 548.13; found 548.9 (M+H).

Embodiment 3

[0244] 5-[4-[(R)-1-(4-chlorophenyl)-ethyl]-7-iodo-2,5-dioxo-(3S)-3-(4-trifluoromethyl- Phenyl)-2,3,4,5-tetrahydrobenzo[e][1,4]diazepin-1-yl]-pentanoic acid

[0245]

[0246] 1 H NMR (400MHz, CDCl 3 )δ7.94(d, J=2.1Hz, 1H), 7.50(d, J=8.4Hz, 2H), 7.44(dd, J=8.6Hz, 2.1Hz, 1H), 7.33(d, J=8.6Hz , 2H), 7.18(d, J=8.4Hz, 2H), 6.68(d, J=8.4Hz, 2H), 6.57(d, J=8.6Hz, 2H), 6.46-6.39(m, 1H), 5.39 (s, 1H), 4.39-4.31(m, 1H), 3.70-3.62(m, 1H), 2.37(t, J=7.0Hz, 2H), 1.75(d, J=7.2Hz, 3H), 1.67- 1.58 (m, 4H). Mass Spectrum (LCMS, ESI pos.): C 29 h 25 CIF 3 IN 2 o 4 Calculated for: 684.05; found 684.8 (M+H).

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Abstract

The present invention is directed to a combinational therapy for treating cancer or other cell proliferative diseases. Such a therapy combines the use of radiation therapy or chemotherapy with the use of a small molecule inhibitor of the MDM2: p53 interaction.

Description

[0001] Cross References to Related Applications [0002] This application is a continuation-in-part of U.S. Application 10 / 829,040, filed April 21, 2004 and U.S. Application, filed November 13, 2002. field of invention [0003] The present invention relates to the field of treatment of cancer or other proliferative diseases. In particular, the invention relates to combination therapy using small molecule inhibitors of the MDM2:p53 interaction. [0004] HDM2 is the expression product of hdm2, an oncogene overexpressed in various cancers, especially soft tissue sarcomas (Momand, J. et al., Nucl. Acids Res. 26:3453-3459 (1998)). [0005] p53 is a transcription factor that plays a critical role in the regulation of the balance between cell proliferation and cell growth arrest / apoptosis. Under normal conditions, the half-life of p53 is very short, so the level of p53 in cells is correspondingly low. However, in response to cellular DNA damag...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K45/06A61K31/4745A61K31/513A61K31/55A61K31/5513A61K31/704A61K31/7072A61P35/00
CPCA61K31/4745A61K31/55A61K31/5513A61K31/704A61K31/7072A61K45/06A61P35/00A61P43/00A61K2300/00
Inventor T·卢H·K·科布利什A·马罗尼
Owner ORTHO MCNEIL PHARM INC