5-aminopyrazol-3-yl-3h-imidazo [4,5-b] pyridine derivatives and their use for the treatment of cancer

An alkyl and alkynyl technology, which can be used in medical preparations containing active ingredients, drug combinations, allergic diseases, etc., and can solve problems such as the increase of prostate cancer

Inactive Publication Date: 2010-03-24
ASTRAZENECA AB
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

For example, although Trk is expressed at low levels outside the nervous system in mature adults, Trk expression is increased in advanced prostate cancer

Method used

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  • 5-aminopyrazol-3-yl-3h-imidazo [4,5-b] pyridine derivatives and their use for the treatment of cancer
  • 5-aminopyrazol-3-yl-3h-imidazo [4,5-b] pyridine derivatives and their use for the treatment of cancer
  • 5-aminopyrazol-3-yl-3h-imidazo [4,5-b] pyridine derivatives and their use for the treatment of cancer

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0613] N-(5-cyclopropyl-1H-pyrazol-3-yl)-6-fluoro-3-[(1S)-1-(5-fluoropyridin-2-yl)-ethyl Base]-3H-imidazo[4,5-b]-pyridin-5-amine

[0614] to N 2 -(5-cyclopropyl-1H-pyrazol-3-yl)-3-fluoro-N 6 -[(1S)-1-(5-fluoropyridin-2-yl)-ethyl]-5-nitropyridine-2,6-diamine (intermediate 8, 300mg, 0.75mmol) in MeOH-THF (19mL , 1:1 ratio) was added zinc powder (245 mg, 3.75 mmol), then saturated NH 4 Cl (water) solution (1.9 mL). The resulting mixture was stirred at ambient temperature for 1 hour. When the reaction shows consumption of starting material, add NH 4 OAc (2.3 mL) solution, and the mixture was stirred at ambient temperature for an additional 30 minutes. Ethyl acetate was added and the mixture was filtered through celite pad. The filtrate was transferred to a separatory funnel and extracted with saturated NaCl(aq) solution. The organic layer was washed with Na 2 SO 4 Dry, filter and concentrate. The residue was dissolved in ethanol (14 mL), then formamidine acetate (1...

Embodiment 2

[0616] N-(5-cyclopropyl-1H-pyrazol-3-yl)-3-[(1S)-1-(5-fluoropyridin-2-yl)ethyl]-3H-imidazole And[4,5-b]pyridin-5-amine

[0617] The title compound was prepared using a procedure similar to that described in Synthetic Example 1, using N 6 -(5-Cyclopropyl-1H-pyrazol-3-yl)-N 2 -[(1S)-1-(5-Fluoropyridin-2-yl)-ethyl]-3-nitropyridine-2,6-diamine (interm. 10) as starting material. The residue was subjected to flash chromatography (Biotage, 7% methanol in dichloromethane) to provide the title compound (86 mg, 55% isolated yield). LCMS (electrospray): 364 [M+1]. 1 H NMR (400MHz, CD 3 OD) δ8.51 (d, 1H) 8.30 (s, 1H) 7.79 (d, 1H) 7.49-7.61 (m, 1H) 7.42 (dd, 1H) 6.73 (d, 1H) 5.99 (d, 1H) 5.77 ( s, 1H) 1.84-1.96 (m, 1H) 0.91-1.03 (m, 2H) 0.65-0.78 (m, 2H).

Embodiment 3

[0619] N-(5-ethoxy-1H-pyrazol-3-yl)-6-fluoro-3-[(1S)-1-(5-fluoropyridin-2-yl)-ethyl base]-3H-imidazo[4,5-b]pyridin-5-amine

[0620] The title compound was prepared using a procedure similar to that described in Synthetic Example 1, using N 2 -(5-ethoxy-1H-pyrazol-3-yl)-3-fluoro-N 6 -[(1S)-1-(5-Fluoropyridin-2-yl)-ethyl]-5-nitropyridine-2,6-diamine (interm. 12) as starting material. The residue was subjected to flash chromatography (Biotage, 30%→50% acetone in dichloromethane) to provide the title compound (70 mg, 8% isolated yield). LCMS (electrospray): 386 [M+1]. 1 H NMRδ8.45(d,1H)8.36(s,1H)7.85(d,1H)7.54-7.69(m,1H)7.48(dd,1H)7.36(d,1H)6.01(s,1H)5.18(t , 1H) 4.07-4.32 (m, 2H) 1.54 (d, 3H) 1.41 (t, 3H).

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Abstract

The present invention relates to compounds of Formula (I) and to their pharmaceutical compositions, and to their methods of use. These novel compounds provide a treatment for myeloproliferative disorders and cancer.

Description

technical field [0001] The present invention relates to novel compounds, their pharmaceutical compositions and their use. In addition, the present invention relates to a therapeutic method for the treatment and prevention of cancer, and the use of said compound in the preparation of a medicament for the treatment and prevention of myeloproliferative diseases and cancer. Background technique [0002] Receptor-type tyrosine kinases (RTKs) are a subfamily of protein kinases that play critical roles in cell signal transduction and are involved in various cancer-related processes including cell proliferation, survival, angiogenesis and metastasis. Up to 100 different RTKs have been identified, including tropomyosin-related kinase (Trk). [0003] Trks are high affinity receptors activated by a group of soluble growth factors called neurotrophins (NT). The Trk receptor family has three members: TrkA, TrkB and TrkC. In NT there are (i) nerve growth factor (NGF), which activates T...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D471/04A61K31/437A61P35/00
CPCC07D471/04A61P9/00A61P9/10A61P13/12A61P17/06A61P19/08A61P27/02A61P29/00A61P35/00A61P35/02A61P37/06A61P43/00
Inventor A·达维斯S·约安尼季斯M·兰布T·王H·-J·张
Owner ASTRAZENECA AB
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