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Synergistic modulation of FLT3 kinase using a farnesyl transferase inhibitor

A kinase inhibitor, tyrosine kinase technology, applied in the field of synergistically modulating FLT3 kinase with alkylquinolines and alkylquinazolines, can solve the problem of shortened symptom remission time, reduced proportion of symptom remission induction, and poor overall prognosis And other issues

Inactive Publication Date: 2008-08-13
JANSSEN PHARMA NV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

More importantly, patients with ITD mutations had a lower proportion of symptomatic remission induction, shorter duration of symptomatic remission, and worse overall prognosis

Method used

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  • Synergistic modulation of FLT3 kinase using a farnesyl transferase inhibitor
  • Synergistic modulation of FLT3 kinase using a farnesyl transferase inhibitor
  • Synergistic modulation of FLT3 kinase using a farnesyl transferase inhibitor

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0719] 4-(6,7-Dimethoxy-quinazolin-4-yl)-piperidine-1-carboxylic acid (4-isopropoxy-phenyl)-amide hydrochloride

[0720]

[0721] a. (4-isopropoxy-phenyl)-carbamic acid 4-nitro-phenyl ester

[0722]

[0723] To a solution of 4-isopropoxyaniline (9.06 g, 60.0 mmol) in DCM (120 mL) and pyridine (30 mL) was added chloroformic acid in portions with stirring under brief ice bath cooling over ~1 min 4-Nitrophenyl ester (10.9 g, 54.0 mmol). After stirring at room temperature for 1 hour, the homogeneous solution was diluted with DCM (300 mL), washed with 0.6M HCl (1 x 750 mL) and 0.025M HCl (1 x 1 L). The organic layer was dried (Na 2 SO 4 ) and concentration to afford the title compound as a light purple-white solid (16.64 g, 98%). 1 H-NMR (300 MHz, CDCl 3 )δ 8.26 (m, 2H), 7.40-7.28 (m, 4H), 6.98 (br s, 1H), 6.87 (m, 2H), 4.50 (heptet, J=6.0 Hz, 1H), 1.33 (d, J =6.0Hz, 6H).LC / MS (ESI): mass calculated 316.1, found 633.2 (2MH) + .

[0724] b. Piperidine-1,4-dicarboxylic ...

Embodiment 2

[0740] 4-(6,7-Dimethoxy-quinazolin-4-yl)-piperidine-1-carboxylic acid (4-iodo-phenyl)-amide

[0741]

[0742] a. (4-iodo-phenyl)-carbamic acid 4-nitro-phenyl ester

[0743]

[0744] The title compound was prepared from 4-iodoaniline essentially as described in Example la except that the reaction was stirred at room temperature for 3 hours. The homogeneous solution was then partitioned with DCM and aqueous HCl essentially as described in Example 1a, except that a heavy precipitate formed in the organic layer. The organic layer was filtered to afford the title compound as an off-white solid (8.50 g, 61%). 1 H-NMR (400 MHz, CDCl 3 ) 8.30 (m, 2H), 7.68 (m, 2H), 7.39 (m, 2H), 7.30-7.20 (m, 2H), 6.98 (br s, 1H).

[0745] b. 4-(6,7-Dimethoxy-quinazolin-4-yl)-piperidine-1-carboxylic acid (4-iodo-phenyl)-amide

[0746]

[0747] 6,7-Dimethoxy-4-piperidin-4-yl-quinazoline (5.18 g, 19.0 mmol) (prepared essentially as described in Example 1d) and (4 -Iodo-phenyl)-carbamic aci...

Embodiment 3

[0749] 4-(6,7-Dimethoxy-quinazolin-4-yl)-piperidine-1-carboxylic acid (4-imidazol-1-yl-phenyl)-amide

[0750]

[0751] a. 4-(6,7-dimethoxy-quinazolin-4-yl)-piperidine-1-carbonyl chloride

[0752]

[0753] To a solution of 1.85 M phosgene in toluene (15.8 mL, 29.3 mmol) and DCM (32 mL) at -78 °C was added 6,7-dimethoxy-4-piperidine-4- Quinazoline (4.00 g, 14.6 mmol) (prepared essentially as described in Example 1d) was immediately followed by the rapid addition of DIEA (2.66 mL, 16.1 mmol) along the side of the flask over ~5 seconds. The flask was sealed and stirred at -78°C for an additional 5 minutes, then the flask was placed in an ice bath and stirred at 0°C for 30 minutes. The opaque, stirrable slurry was then poured into a mixture of DCM (70 mL), 0.5M trisodium citrate (60 mL) and ice (60 mL) and partitioned. The aqueous layer was extracted with DCM (1×50 mL), and the organic layers were combined and dried (Na 2 SO 4), and concentration under reduced pressure to...

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Abstract

The present invention relates to a method for inhibiting FLT3 tyrosine kinase activity or expression in a cell or a subject, or reducing FLT3 kinase activity or expression, comprising administering a farnesyl transferase inhibitor and an alkyl selected from formula (I') FLT3 kinase inhibitors of alkylquinolines and alkylquinazolines: where R 1 , R 2 , R 3 , Z, G, Q and X are as defined herein. The invention includes prophylactic and therapeutic methods for treating subjects at risk of (or susceptible to) developing a cell proliferative disorder or a FLT3-related disorder.

Description

[0001] Cross References to Related Applications [0002] This application claims priority to US Provisional Patent Application 60 / 690,070, filed June 10, 2005, which is hereby incorporated in its entirety. field of invention [0003] The present invention relates to the use of farnesyltransferase inhibitors in combination with FLT3 tyrosine kinase inhibitors for the treatment of cell proliferative disorders or FLT3-related disorders. Background of the invention [0004] Fms-like tyrosine kinase 3 (FLT3) ligand (FLT3L) is one of the cytokines affecting the development of various hematopoietic lineages. These effects are mediated by the binding of FLT3L to the FLT3 receptor, also known as fetal liver kinase-2 (flk-2), and STK-1, a receptor tyrosine kinase (RTK) expressed on hematopoietic stem and progenitor cells. occur. During normal hematopoiesis, the FLT3 gene encodes a transmembrane class III RTK that plays an important role in cell proliferation, differentiation and ap...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/517A61K31/4709A61K31/00A61P35/00C12N5/07C12N5/077C12N5/09
CPCA61K31/00A61K31/4709A61K31/496A61K31/517A61K31/5377A61K31/541A61K45/06A61P35/00A61P35/02A61P43/00A61P7/00A61K2300/00
Inventor C·A·鲍曼M·D·高尔R·W·图曼D·L·约翰逊
Owner JANSSEN PHARMA NV
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