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Pyrrolopyrimidine compounds and uses thereof

A compound, selected technology, applied in the fields of organic chemistry, drug combination, organic chemistry methods, etc., can solve problems such as unknown genetic basis of disease

Inactive Publication Date: 2013-05-22
HUTCHISON MEDIPHARMA LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Although myeloproliferative disorders (eg, PV, ET, and MMM) are thought to result from acquired somatic mutations in hematopoietic progenitor cells, the genetic basis of these disorders is unknown

Method used

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  • Pyrrolopyrimidine compounds and uses thereof
  • Pyrrolopyrimidine compounds and uses thereof
  • Pyrrolopyrimidine compounds and uses thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0281] Embodiment 1: the synthesis of compound 1-260

[0282] Compound 1

[0283] (R)-N-(1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrrolidin-3-yl)-2-cyano-N-methylacetamide

[0284]

[0285] To (R)-N-methyl-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrrolidin-3-amine (75mg, 0.345mmol) and 2-cyanoacetic acid (35mg , 0.414 mmol) in THF (5 mL) were added HATU (157 mg, 0.414 mmol) and DIPEA (0.12 mL, 0.69 mmol). The reaction mixture was stirred at room temperature for 20 hours. The precipitate was filtered, washed with EtOAc and dried under reduced pressure to give the title compound (45 mg, 46%). MS(m / z):285(M+H) + .

[0286] The following compounds were prepared according to the operation of Compound 1 using corresponding intermediates and reagents under suitable conditions recognized by those skilled in the art.

[0287]

[0288]

[0289] Compound 9

[0290] (R)-N-(1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrrolidin-3-yl)-4-cyano-N-methylbenzenesulfonamide

[0291]

[0292] To...

Embodiment 2

[0539] Enzyme assay

[0540] JAK1 / 2 / 3 kinase assays were performed in vitro with Kit-Tyr6 Peptide (Invitrogen, cat# PV4122). With Z'-LYTE TM The Kinase Assay Kit-Tyr3Peptide (Invitrogen, Cat# PV3192) was used to perform the TYK2 kinase assay in vitro. Recombinant human JAK1 / 2 / 3 or TYK2 catalytic domains were from Invitrogen (catalogue # PV4774 / PV4210 / PV3855 / PV4790); all reactions (20 μL) were initiated by adding: 2.5 μL of test compound in 4% DMSO solution, 5 μL kinase / peptide substrate mix (3.2, 0.04, 0.2 or 8 μg / mL for recombinant human JAK1 / 2 / 3 catalytic domain, for Z-LYTE TM Tyr6Peptide or Z-LYTE TM Tyr3Peptide is 4 μM) or Phospho-Peptide solution (Invitrogen, catalog number PV3192, diluted with 1.33x kinase buffer), 2.5 μL ATP solution (300 / 100 / 40 / 100 μM, JAK1 / JAK2 / JAK3 / TYK2) or 1.33 x Kinase Buffer (Invitrogen, catalog number PV3189, diluted 5-fold with distilled water). A 384-well assay plate (Corning, Cat# 3575) was mixed and incubated for 1 hour at room temperatu...

Embodiment 3

[0543] Cytometry

[0544] To measure IL-6-induced STAT3 phosphorylation, HepG2 cells (SIBS) were cultured in serum-free DMEM medium at 5.4×10 3 cells / well were seeded overnight in 96-well plates at 37°C, 5% CO in the presence or absence of various concentrations of diluted compounds. 2 Incubate for 30 minutes. At 37°C, 5% CO 2 Next, cells were stimulated for 15 minutes by adding 10 ng / ml human recombinant IL-6 to each well. Cells were then fixed with 2% paraformaldehyde for 45 minutes at room temperature and incubated in ice-cold methanol for 30 minutes. After washing with PBS, cells were incubated overnight at 4°C with rabbit anti-phospho-STAT3 (Y705) (Cell Signaling Technologies, 1:1000, in antibody dilution solution) primary antibody. Goat anti-rabbit IgG Alexa488 (Invitrogen, 1:1000 dilution in PBS) secondary antibody was added and washed with PBS. Cells were counted after incubating in 7.5 uM propidium iodide, 100 μg / ml RNaseA, and PBS solution for 60 minutes in the ...

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Abstract

Disclosed are pyrrolopyrimidine compounds of formula (I) capable of inhibiting JAK kinase, wherein R1, R2 and m are defined as in the description. The pharmaceutical compositions containing said pyrrolopyrimidine compounds and uses of said pyrrolopyrimidine compounds in the treatment of disorders or diseases such as inflammatory diseases and cancers are also disclosed.

Description

technical field [0001] The present invention relates to the field of medicine. For example, the present invention relates to certain pyrrolopyrimidine compounds, compositions containing said compounds, and uses thereof. These pyrrolopyrimidine compounds can effectively inhibit the activity of JAK kinase. Background technique [0002] The Janus kinase (JAK) family is one of the well-known non-receptor tyrosine kinase families. The JAK family can be activated by the binding of cytokines to cell surface receptors. Activated Jak can then initiate intracellular signaling cascades. The Jak family and Signal Transducers and Activators of Transcription (STAT) are involved in the signaling pathways of many cytokines. [0003] The JAK / STAT pathway has been shown to play a role in inflammatory diseases such as airway inflammatory disease, multiple sclerosis, rheumatoid arthritis, asthma, inflammatory bowel disease, allergy, autoimmune disease and other immune responses. JAK / STAT p...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D487/04C07D403/14C07D403/04C07D405/14C07D405/04C07D413/14C07D401/04C07D401/14A61K31/519A61P29/00A61P35/00
CPCC07D471/04C07D487/04A61K31/519A61K31/5377A61P29/00A61P35/00A61P43/00C07D403/14A61K45/06C07B2200/07
Inventor 苏慰国邓伟李金水纪建国
Owner HUTCHISON MEDIPHARMA LTD
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