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Pyrrolopyrimidine compound and use thereof

A compound and pharmaceutical technology, applied in the field of pyrrolopyrimidine compounds, can solve the problems of unclear gene mechanism and variation, etc.

Inactive Publication Date: 2012-03-14
HUTCHISON MEDIPHARMA LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

It is generally believed that MPD is caused by in vivo mutations in hematopoietic stem cells, but the genetic mechanism of disease formation is still unclear, but studies have found that most PV patients and a considerable number of ET and MMM patients have periodic in vivo mutations in the JAK2 kinase of hematopoietic cells

Method used

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  • Pyrrolopyrimidine compound and use thereof
  • Pyrrolopyrimidine compound and use thereof
  • Pyrrolopyrimidine compound and use thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0260] Embodiment 1: the synthesis of compound 1-260

[0261] Compound 1

[0262] (R)-N-(1-(7H-pyrrolo[2,3-d]pyrimidine-4-)pyrrolidine-3-)-2-cyano-N-methylacetamide

[0263]

[0264] (R)-N-Methyl-1-(7H-pyrrolo[2,3-d]pyrimidine-4-)pyrrolidin-3-amine (75mg, 0.345mmol) and cyanoacetic acid (35mg, 0.414mmol ) was dissolved in tetrahydrofuran (5 mL), HATU (157 mg, 0.414 mmol) and DIPEA (0.12 mL, 0.69 mmol) were added, and stirred at room temperature for 20 hours. The precipitated solid was filtered, the filter cake was washed with ethyl acetate and dried under reduced pressure to obtain the target product (45 mg, 46%). MS (m / z): 285 (M+H) + .

[0265] Compounds 2-8 can be prepared by those skilled in the art using corresponding intermediates and reagents under appropriate conditions, and the specific synthesis method can refer to compound 1.

[0266]

[0267]

[0268] Compound 9

[0269] (R)-N-(1-(7H-pyrrolo[2,3-d]pyrimidine-4-)pyrrolidine-3-)-4-cyano-N-methylbenzenesul...

Embodiment 2

[0525] Enzyme activity detection

[0526] With Z'-LYTE TM Kinase Assay Kit-Tyr 6 Peptide (Invitrogen, Cat. No. PV4122) kit was used to analyze JAK1 / 2 / 3 kinase activity. With Z'-LYTE TM Kinase Assay Kit-Tyr 3Peptide (Invitrogen, Cat. No. PV3192) kit was used to analyze TYK2 kinase activity. Recombinant human JAK1 / 2 / 3 or TYK2 kinases were purchased from Invitrogen (Cat No. PV4774 / PV4210 / PV3855 / PV4790); 20 μL total reaction solution as follows, containing 2.5 μL test compound dissolved in 4% DMSO, 5 μL enzyme / substrate mix Buffer (containing 3.2, 0.04, 0.2, 8 μg / mL recombinant human JAK1 / 2 / 3 or TYK2 kinase, 4 μM Tyr 6 or Tyr 3 reaction substrate peptide) or Tyr 6 or Tyr 3 phosphorylation substrate buffer (Invitrogen, Cat.No.PV3192, diluted with 1.33x kinase buffer), 2.5 μL ATP solution (300 / 100 / 40 / 100 μM, JAK1 / 2 / 3 or TYK2 kinase) or 1.33x kinase buffer (Invitrogen, Cat.No.PV3189 , 5x kinase buffer, diluted with water). Mix the components in the reaction wells (total volume...

Embodiment 3

[0529] cell detection

[0530] In order to detect IL6-induced phosphorylated STAT3 levels, HepG2 cells (SIBS) were resuspended in serum-free DMEM medium at 5.4×10 3 Cells were seeded in 96-well plates and incubated overnight in a cell culture incubator. The next day, various concentrations of compounds were added, and after incubation for 30 minutes, human recombinant IL6 with a final concentration of 10 ng / ml was added to stimulate for 15 minutes. The cells were then fixed with 2% paraformaldehyde at room temperature for 45 minutes, incubated with ice-cold methanol for another 30 minutes, washed with PBS, and incubated with rabbit anti-phosphorylated STAT3 (Y705) (Cell Signaling Technologies) primary antibody overnight at 4°C. After washing, incubate with goat anti-rabbit IgG Alexa 488 secondary antibody for 90 minutes. Add 7.5uM propidium iodide (containing 100g / ml RNaseA) and stain in the dark for 60 minutes, and read the plate with an Acumen X3 (TPPLabtech) instrument. ...

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Abstract

The present invention provides a pyrrolopyrimidine compound and a use thereof. Specifically that the present invention provides a class of pyrrolopyrimidine compounds with the inhibitory activity of JAK kinase. The present invention further provides a drug composition containing the pyrrolopyrimidine compound, and an application of the drug composition in treatments of inflammatory diseases, cancer and other diseases.

Description

technical field [0001] The invention relates to the field of medicines, and more specifically, the invention relates to a class of pyrrolopyrimidine compounds with JAK kinase inhibitory activity and uses thereof. Background technique [0002] The JAK (Janus kinase) family belongs to non-receptor tyrosine kinases. Specific cytokines bind to cell surface receptors, activate JAKs, and subsequently initiate a series of intracellular signaling cascades. The JAK kinase family and signal transducers and activators of transcription (STATs) are involved in the signal transduction process of many cytokines. [0003] The JAK / STAT signaling pathway is associated with many inflammatory diseases, such as: respiratory inflammation, multiple sclerosis, rheumatoid arthritis, asthma, enteritis, allergy, autoimmune diseases and other inflammatory responses. JAK / STAT signaling pathways, such as the JAK3 / STAT signaling pathway, are also associated with certain cancer diseases. [0004] Theref...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D487/04C07D519/00A61K31/519A61K31/635A61K31/5377A61P29/00A61P35/00
Inventor 苏慰国邓伟李金水纪建国
Owner HUTCHISON MEDIPHARMA LTD
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