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Compound with Janus kinase inhibitory activity, composition comprising compound and application of compound

A kind of kinase inhibition and compound technology, applied in the field of medicine, to achieve the effect of excellent pharmacodynamic performance and excellent Janus kinase inhibitory activity

Active Publication Date: 2022-04-22
上海邈金医药科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

However, the research is still in progress and more tests will be needed later to verify the drug's safety

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  • Compound with Janus kinase inhibitory activity, composition comprising compound and application of compound
  • Compound with Janus kinase inhibitory activity, composition comprising compound and application of compound
  • Compound with Janus kinase inhibitory activity, composition comprising compound and application of compound

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preparation example Construction

[0079] The preparation of solvates and hydrates is well known in the art, a typical procedure is as follows: Dissolving the compound in the required amount of solvent (organic solvent, water or a mixture of both) at above ambient temperature In this method, the solution is cooled at a rate sufficient to form crystals, the crystals are then isolated by standard methods, and finally the presence of solvent or water in the crystals of the solvate or hydrate is confirmed by analytical techniques (eg, infrared spectroscopy, thermal analysis).

[0080] Since the above compound has excellent Janus kinase inhibitory activity, it can be used as a medicament for preventing and / or treating autoimmune diseases, inflammatory diseases, allergies, cancer, skin diseases, and myelofibrosis.

[0081] In a preferred embodiment of the present invention, the above-mentioned autoimmune diseases are autoimmune skin disorders, multiple sclerosis, rheumatoid arthritis, juvenile arthritis, type I diabet...

Embodiment 1

[0097] This example provides the compound (3S,4R)-3-fluoromethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazine- 8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-amide (C), its preparation process is as follows (wherein the synthetic route of compound C is as follows figure 1 ):

[0098] step 1:

[0099]

[0100] Under nitrogen protection, a solution of compound 1 (10.0 g, 71.3 mmol, 1.0 eq) in anhydrous THF (200 mL) was cooled to -68°C with a dry ice-acetone bath. To the above solution, n-BuLi (29.1 mL, 2.5M in hexane, 72.8 mmol, 1.05 eq) was slowly added dropwise, and the addition was completed in 45 minutes. Subsequently, it was stirred at -65°C for 1 hour. Compound S1 (11.6 g, 107.0 mmol, 1.5 eq) was added dropwise to the above reaction liquid. After dropping, stir at -65°C for 0.5 hours. TLC detection showed that the reaction was complete.

[0101] The reaction solution was quenched with aqueous ammonium chloride (100 mL). Separate the organic phase. The aqueous phase w...

Embodiment 2

[0162] This example provides the compound (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazine-8- Base)-N-(2-fluoro-2-methylpropyl)pyrrolidin-1-amide (D), its preparation process is as follows (such as figure 2 ):

[0163] step 1:

[0164]

[0165] Under nitrogen protection, NaH (0.345 g, 8.61 mmol, 1.0 eq) was slowly added to anhydrous DMF (10 mL), and the ice-salt bath was cooled to 0°C. To the above system, 10 mL of DMF solution of compound a (3.35 g, 8.61 mmol, 1.0 eq) was slowly added dropwise, and the temperature of the addition was controlled not to exceed 0°C. After the addition, the reaction was continued for 30 minutes. Then, 10 mL of DMF solution of compound D-1 (3.05 g, 8.61 mmol, 1.0 eq) was added dropwise to the system, and stirring was continued at 0° C. for 1.5 hours after the addition was complete. TLC showed complete consumption of starting material D-1. The reaction was quenched with 0.2 L of ice water, extracted with ethyl acetate (50 mL×3), a...

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Abstract

The invention provides a compound with Janus kinase inhibitory activity, a composition containing the compound and application of the compound. The compound is a 4-(3H-imidazo [1, 2-a] pyrrolo [2, 3-e] pyrazine-8-yl)-pyrrolidine-1-amide compound as shown in a formula I or a derivative thereof, and the derivative is a pharmaceutically acceptable salt, ester, prodrug, single crystal or polymorphic substance, solvate or hydrate thereof. The 4-(3H-imidazo [1, 2-a] pyrrolo [2, 3-e] pyrazine-8-yl)-pyrrolidine-1-amide compound or the derivative thereof provided by the invention has excellent Janus kinase inhibition activity and excellent pharmacodynamic performance, and can be used as a Janus kinase inhibitor to provide a new effective choice for treating related diseases.

Description

technical field [0001] The invention relates to the field of medicine, in particular to a compound with Janus kinase inhibitory activity, a composition comprising the compound and applications thereof. Background technique [0002] Janus kinase inhibitors, also known as JAK inhibitors or jakinibs [1] , is a drug that acts by inhibiting the activity of one or more Janus kinase family enzymes (JAK1, JAK2, JAK3, TYK2), thereby interfering with / blocking the JAK-STAT signaling pathway. JAK-STAT signaling pathway is a signal transduction pathway stimulated by cytokines discovered in recent years, which is involved in many important biological processes such as cell proliferation, differentiation, apoptosis and immune regulation. Janus kinase (JAK) inhibitors have been developed as drugs for the treatment of diseases such as hematological diseases, tumors, rheumatoid arthritis and inflammatory diseases such as vitiligo and psoriasis [1][2] , such as rheumatoid arthritis [3] . T...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D487/14A61P37/06A61P29/00A61P37/08A61P35/00A61P17/00A61P19/02A61P3/10A61P1/00A61P1/04A61P21/04A61P13/12A61P9/00A61P5/14A61P35/02A61K31/4985
CPCC07D487/14A61P37/06A61P29/00A61P37/08A61P35/00A61P17/00A61P19/02A61P3/10A61P1/00A61P1/04A61P21/04A61P13/12A61P9/00A61P5/14A61P35/02C07B2200/07
Inventor 彭伟陈兴海李旻明
Owner 上海邈金医药科技有限公司
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