Synergistic modulation of FLT3 kinase using thienopyrimidine and thienopyridine kinase modulators

A kinase inhibitor, tyrosine kinase technology, applied in the field of co-modulation of FLT3 kinase using thienopyrimidines and thienopyridine kinase regulators, can solve the problem of reduced induction ratio of symptom remission, shortened time of symptom remission, 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 thienopyrimidine and thienopyridine kinase modulators
  • Synergistic modulation of FLT3 kinase using thienopyrimidine and thienopyridine kinase modulators
  • Synergistic modulation of FLT3 kinase using thienopyrimidine and thienopyridine kinase modulators

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0650] (4-Isopropyl-phenyl)-carbamic acid 1-thieno[2,3-d]pyrimidin-4-yl-piperidin-4-yl ester

[0651]

[0652] a.1-thieno[2,3-d]pyrimidin-4-yl-piperidin-4-ol

[0653]

[0654] A solution of 4-chloro-thieno[2,3-d]pyrimidine (85.3 mg, 0.502 mmol) in isopropanol (2 mL) was treated with 4-hydroxypiperidine (50.6 mg, 0.501 mmol). After stirring at 100 °C overnight, the reaction was cooled to RT and 2 O (20mL). Na for organic phase 2 SO 4 Drying and concentration in vacuo afforded the title compound as a solid (67.8 mg, 58%) which was used in the next step without further purification or characterization.

[0655] b. (4-Isopropyl-phenyl)-carbamic acid 1-thieno[2,3-d]pyrimidin-4-yl-piperidin-4-yl ester

[0656]

[0657] To a solution of 1,1'-carbonyldiimidazole (23.5 mg, 0.145 mmol) in DCM (1 mL) was added 4-isopropylaniline (19.6 mg, 0.145 mmol). After stirring at 0 °C for 2 hours, 1-thieno[2,3-d]pyrimidin-4-yl-piperidin-4-ol (34.1 mg, 0.145 mmol) prepared in the...

Embodiment 2

[0659] (4-Isopropoxy-phenyl)-carbamic acid 1-thieno[2,3-d]pyrimidin-4-yl-piperidin-4-yl ester

[0660]

[0661] To a solution of 1,1'-carbonyldiimidazole (23.3 mg, 0.144 mmol) in DCM (1 mL) was added 4-isopropoxyaniline (21.7 mg, 0.144 mmol). After stirring at 0° C. for 2 hours, 1-thieno[2,3-d]pyrimidin-4-yl-piperidin-4-ol (33.7 mg, 0.143 mmol) prepared in Example 1a was added, and in Stir at RT. After 2 hours, DMAP (17.6 mg, 0.144 mmol) was added and stirred at 85 °C overnight. The reaction was then cooled to RT and dissolved in DCM (10 mL) and H 2 O (10mL). Na for organic phase 2 SO 4 Dry and concentrate in vacuo. Purification by preparative tlc (1:1 hexanes / EtOAc) afforded the title compound as a light green solid (8.4 mg, 14%). 1 H NMR (300MHz, CDCl 3 )δ8.7 (brs, 1H), 7.44 (brm, 1H), 7.29 (m, 3H), 6.85 (m, 2H), 6.56 (brs, 1H), 5.09 (m, 1H), 4.48 (heptet, 1H ), 4.17(m, 2H), 3.75(m, 2H), 2.11(m, 2H), 1.87(m, 2H), 1.31(d, 6H).LC / MS(ESI): mass calculated value...

Embodiment 3

[0663] (4-Isopropyl-phenyl)-carbamic acid 1-thieno[2,3-d]pyrimidin-4-yl-pyrrolidin-3-yl ester

[0664]

[0665] (4-Isopropyl-phenyl)-carbamic acid 4-nitro-phenyl ester

[0666]

[0667] To a solution of 4-isopropylaniline (3.02 g, 22.3 mmol) in DCM (40 mL) and pyridine (10 mL) was added portionwise 4-nitrophenylchloroformate with stirring over approximately 30 seconds under simple ice bath cooling base ester (4.09 g, 20.3 mmol). After stirring at room temperature for 1 hour, the homogeneous solution was diluted with DCM (100 mL) and 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 SO 4 ) and concentrated to afford the title compound as a pale pink solid (5.80 g, 95%). 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). LC / MS (ESI): Mass calculated 300.1, found 601.3 (2MH) + .

[0668] b. (4-I...

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Abstract

The present invention relates to a method for inhibiting the activity or expression of FLT3 tyrosine kinase in a cell or a subject, or reducing the activity or expression of FLT3 kinase, comprising administering a farnesyl transferase inhibitor and a compound selected from formula I' and formula II' FLT3 kinase inhibitors of thienopyrimidines and thienopyridines: where R 1 , R 3 , B, Z, Q, p, 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 / 689,409, 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): A61K31/519A61P35/00A61K31/517A61K31/4709A61K31/506A61K31/00
CPCA61K31/506A61K31/00A61K31/519A61K31/4743A61K31/4709A61K31/517A61K45/06A61P19/08A61P35/00A61P35/02A61P43/00A61K2300/00C07D495/04
Inventor C·A·鲍曼M·D·高尔
Owner JANSSEN PHARMA NV
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