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Synergistic modulation of FLT3 kinase using aminoquinoline and aminoquinazoline kinase modulators

A technology of kinase inhibitor and tyrosine kinase, which is used in medical preparations containing active ingredients, pharmaceutical formulations, anti-tumor drugs, etc.

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

To date, there are no strong favorable data to support that kinase domain point mutations or overexpressed wild-type receptors are the cause of disease, but FLT3 expression may be a factor in disease development

Method used

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  • Synergistic modulation of FLT3 kinase using aminoquinoline and aminoquinazoline kinase modulators
  • Synergistic modulation of FLT3 kinase using aminoquinoline and aminoquinazoline kinase modulators
  • Synergistic modulation of FLT3 kinase using aminoquinoline and aminoquinazoline kinase modulators

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0771] (4-Isopropyl-phenyl)-carbamic acid 1-(6,7-dimethoxy-quinazolin-4-yl)-piperidin-4-yl ester (Compound No. 1)

[0772]

[0773] Add 1-(6,7-dimethoxy-quinazolin-4-yl)-piperidin-4-ol (29 mg, 0.1 mmol) prepared in Example 3a, 4- Cumyl phenyl ester (20 mg, 0.12 mmol) and dichloroethane (1 mL). After the mixture was stirred at 60°C for 16 hours, the contents were subjected to aqueous workup and purification by TLC to obtain the desired product in 65% yield.

[0774] 1 H NMR (300MHz, CDCl 3 )δ8.67(s, 1H), 7.33-7.25(m, 3H), 7.18(d, J=7.6Hz, 2H), 7.09(s, 1H), 6.64(s, 1H), 5.08(m, 1H ), 4; 02(s, 3H), 3.99(s, 3H), 3.95-3.89(m, 2H), 3.55-3.48(m, 2H), 2.88(sept, J=6.1Hz, 1H), 2.22- 2.14(m, 2H), 2.04-1.91(m, 2H), 1.23(d, J=6.1Hz, 6H);

[0775] LC / MS (ESI): theoretical mass 450.2, found 451.6 (M+H) + .

Embodiment 2

[0777] (4-Isopropyl-phenyl)-carbamic acid 1-(6,7-dimethoxy-quinazolin-4-yl)-pyrrolidin-3-yl ester (Compound No. 2)

[0778]

[0779] a. (4-isopropyl-phenyl)-carbamic acid 4-nitro-phenyl ester

[0780]

[0781] To a solution of 4-isopropylaniline (3.02 g, 22.3 mmol) in DCM (40 mL) and pyridine (10 mL) was added portionwise 4-nitrochloroformic acid with stirring under brief ice bath cooling over ~30 seconds phenyl phenyl ester (4.09 g, 20.3 mmol). After stirring at room temperature for 1 h, the homogeneous solution was diluted with DCM (100 mL), washed with 0.6M HCl (1×250 mL), 0.025M HCl (1×400 mL), water (1×100 mL) and 1M NaHCO 3 (1 x 100 mL) wash. The organic layer was dried (Na 2 8O 4 ), concentrated to afford the title compound as a pale pink solid (5.80 g, 95%).

[0782] 1 H NMR (300MHz, CDCl 3 )δ8.28(m, 2H), 7.42-7.32(m, 4H), 7.23(m, 2H), 6.93(brs, 1H), 2.90(h, J=6.9Hz, 1H), 1.24(d, J =6.9Hz, 6H).

[0783] LC / MS (ESI): theoretical mass 300.1, found 601.3 (2...

Embodiment 3

[0790] (4-Isopropoxy-phenyl)-carbamic acid 1-(6,7-dimethoxy-quinazolin-4-yl)-piperidin-4-yl ester (compound No. 3)

[0791]

[0792] a.1-(6,7-dimethoxy-quinazolin-4-yl)-piperidin-4-ol

[0793]

[0794] A solution of 4-hydroxypiperidine (40.4 mg, 0.400 mmol) in isopropanol (1 mL) was treated with 4-chloro-6,7-dimethoxy-quinazoline (89.9 mg, 0.401 mmol). After stirring overnight at 100 °C, the reaction was cooled to room temperature and dissolved in DCM (10 mL) and H 2 O (10mL). Na 2 SO 4 Dry and concentrate in vacuo to afford the title compound as a solid (60 mg, 52%).

[0795] b. (4-Isopropoxy-phenyl)-carbamic acid 1-(6,7-dimethoxy-quinazolin-4-yl)-piperidin-4-yl ester

[0796]

[0797] Add 1-(6,7-dimethoxy-quinazolin-4-yl)-piperidin-4-ol (29 mg, 0.1 mmol) prepared substantially according to Example 3a, chloroformic acid p-nitrogen to the bottle phenyl phenyl ester (24 mg, 0.12 mmol), triethylamine (20 mg, 0.2 mmol) and dichloroethane (1 mL). After the mixture ...

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Abstract

The invention relates to a method for inhibiting FLT3 tyrosine kinase activity or expression, or reducing FLT3 kinase activity or expression in cells or patients, the method comprising administering a farnesyltransferase inhibitor and a FLT3 kinase inhibitor, wherein the FLT3 kinase inhibitor is selected from Aminoquinoline and aminoquinazoline compounds of formula (I'): wherein R1, R2, R3, B, Z, Q, p, q and X are as defined herein. The present invention includes prophylactic and therapeutic methods of treating patients at risk of (or susceptible to) developing a cell proliferative disorder or a disorder associated with FLT3.

Description

[0001] Related Application Cross Reference [0002] This application claims priority to US Patent Provisional Application No. 60 / 689,721, filed June 10, 2005, the entire contents of which are hereby incorporated by reference in their entirety. field of invention [0003] The present invention relates to the combination treatment of farnesyltransferase inhibitors and FLT3 tyrosine kinase inhibitors for cell proliferative disorders or disorders associated with FLT3. Background of the invention [0004] Fms-like tyrosine kinase 3 (FLT3) ligand (FLT3L) is one of the cytokines affecting the development of multiple hematopoietic lineages. These effects are produced through 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. ). The FLT3 gene encodes transmembrane group III RTKs, which play important roles in cell proliferation, differentiation and ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/4709A61K31/517A61P35/00
CPCA61K31/4709A61K31/517A61K45/06A61P35/00A61P35/02A61P7/00A61K2300/00A61K31/4725
Inventor C·A·鲍曼M·D·高尔
Owner JANSSEN PHARMA NV
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