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Synergistic modulation of FLT3 kinase using aminopyrimidines kinase modulators and a farnesyl transferase inhibitor

A technology of farnesyltransferase and kinase inhibitor, which is applied in the field of synergistic regulation of FLT3 kinase with aminopyrimidine kinase modulator and farnesyltransferase inhibitor

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 aminopyrimidines kinase modulators and a farnesyl transferase inhibitor
  • Synergistic modulation of FLT3 kinase using aminopyrimidines kinase modulators and a farnesyl transferase inhibitor
  • Synergistic modulation of FLT3 kinase using aminopyrimidines kinase modulators and a farnesyl transferase inhibitor

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0627] N-(4-isopropoxy-phenyl)-4-[6-amino-5-(methoxyimino-methyl)-pyrimidin-4-yl]-piperazine-1-carboxamide

[0628]

[0629] a. 4,6-dichloro-pyrimidine-5-carbaldehyde

[0630]

[0631] At 0 °C, DMF (3.2 mL) and POCl 3 (10 mL) was stirred for 1 h, treated with 4,6-dihydroxypyrimidine (2.5 g, 22.3 mmol) and stirred at room temperature for 0.5 h. The heterogeneous mixture was heated to reflux for 3h and the volatiles were removed under reduced pressure. The residue was poured into ice water and extracted 6 times with ether. The organic phase was washed with NaHCO 3 Washed with aqueous solution, Na 2 SO 4 Drying and concentration gave a yellow solid (3.7 g, 95%).

[0632] 1 H NMR (CDCl 3 )δ10.46(s, 1H), 8.90(s, 1H),

[0633] b. 4-Amino-6-chloro-pyrimidine-5-carbaldehyde

[0634]

[0635] Ammonia was bubbled through a solution of 4,6-dichloro-pyrimidine-5-carbaldehyde (1 g, 5.68 mmol) in toluene (100 mL) for 10 min, and the solution was stirred at room temperatur...

Embodiment 2

[0680] N-(4-isopropoxy-phenyl)-4-{6-amino-5-[(2-morpholin-4-yl-ethoxyimino)-methyl]-pyrimidin-4-yl }-piperazine-1-carboxamide

[0681]

[0682] a. 4-Amino-6-piperazin-1-yl-pyrimidine-5-carbaldehyde trifluoroacetate

[0683]

[0684] 4-(6-Amino-5-formyl-pyrimidin-4-yl)-piperazine-1-carboxylic acid tert-butyl ester (235 mg, 0.76 mmol) was dissolved in 50% TFA / CH 2 Cl 2 (10 mL) and the mixture was stirred overnight. Evaporation under reduced pressure afforded a white solid as a pure product which was directly used in the next reaction.

[0685] 1 H NMR (CD 3 OD) δ9.83(s, 1H), 8.29(s, 1H), 4.22(t, J=5.23Hz, 4H), 3.42(t, J=5.42Hz, 4H);

[0686] LC / MS (ESI) C 9 h 14 N 5 O(MH) + The theoretical value is 208.1, and the measured value is 208.1.

[0687] b. N-(4-isopropoxy-phenyl)-4-(6-amino-5-formyl-pyrimidin-4-yl)-piperazine-1-carboxamide

[0688]

[0689] To 4-amino-6-piperazin-1-yl-pyrimidine-5-carbaldehyde trifluoroacetate (0.76mmol) and (4-isopropoxy-phenyl)-ca...

Embodiment 3

[0708] N-(4-isopropoxy-phenyl)-4-{6-amino-5-[(3-hydroxy-propoxyimino)-methyl]-pyrimidin-4-yl}-piperazine- 1-formamide

[0709]

[0710] a. Diphenyl-methanone O-(3-hydroxy-propyl)-oxime

[0711]

[0712] Prepared according to the synthesis method of Example 2c.

[0713] 1 H NMR (CDCl 3 )δ7.30-7.52(m, 10H), 4.35(t, J=5.83Hz, 2H), 3.73(t, J=5.85Hz, 2H), 1.95(m, 2H).

[0714] b. 3-aminooxy-propan-1-ol hydrochloride

[0715]

[0716] Prepared according to the synthesis method of Example 2d.

[0717] 1 H NMR (CD 3 OD) δ4.26(t, J=6.75Hz, 2H), 3.66(t, J=6.11Hz, 2H), 2.51(m, 2H).

[0718] c.N-(4-isopropoxy-phenyl)-4-{6-amino-5-[(3-hydroxy-propoxyimino)-methyl]-pyrimidin-4-yl}-piperazine- 1-formamide

[0719]

[0720] Prepared as described in Example 2e except substituting 3-aminooxy-propan-1-ol for O-(2-morpholin-4-yl-ethyl)-hydroxylamine.

[0721] 1 H NMR (CD 3 OD) δ8.22(s, 1H), 8.08(s, 1H), 7.21(d, J=8.95Hz, 2H), 6.83(d, J=9.01Hz, 2H), 4.52(m, 1H), 4.28 (t, ...

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Abstract

The present invention relates to a method for inhibiting the activity or expression of FLT3 tyrosine kinase in cells or patients, or reducing the activity or expression of FLT3 kinase, the method comprising administering a farnesyltransferase inhibitor and a FLT3 kinase inhibitor, the FLT3 kinase inhibitor being selected from Aminopyrimidine compounds of formula I'; wherein R3, B, Z, r and R1 are as defined herein. The invention also includes prophylactic and therapeutic methods of treating patients at risk of developing (or susceptible to) 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): A61K31/4709A61K45/06A61K31/506A61P35/00
CPCA61K9/0019A61K9/2018A61K31/4709A61K31/506A61K45/06A61P35/00A61P35/02A61P43/00A61K2300/00A61K31/501
Inventor C·A·鲍曼M·D·高尔
Owner JANSSEN PHARMA NV
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