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Heterocyclic Janus kinase 3 inhibitors

A kind of technology of heterocycloalkyl and heteroaryl, applied in the field of immunological disease therapeutic agents, can solve the problems such as no specific disclosed compounds

Active Publication Date: 2009-01-21
ASTELLAS PHARMA INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0013] However, in all of the above-mentioned documents, the compounds of the present invention are not specifically disclosed

Method used

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  • Heterocyclic Janus kinase 3 inhibitors
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  • Heterocyclic Janus kinase 3 inhibitors

Examples

Experimental program
Comparison scheme
Effect test

preparation example 1

[0163] According to a method similar to the method described in Example 1 using the corresponding starting compounds, the compounds in Preparation Examples 1-1 to 1-25 shown in the table below were prepared.

[0164] Table 2

[0165]

[0166] Table 2 (continued)

[0167]

[0168] Table 2 (continued)

[0169]

[0170] table 3

[0171] Preparation example

[0172] Table 3 (continued)

[0173] Preparation example

[0174] 1-9

preparation example 2

[0176] 3-(4-Chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)-1,2,4-oxadiazole-5-carboxylic acid ethyl ester (60mg) in 1-methyl - A solution of 2-pyrrolidone (0.6ml) and 1,8-diazabicyclo[5.4.0]undec-7-ene (0.092ml) was added to glycinamide hydrochloride (34mg) , and the resulting mixture was stirred at 70 °C for 1 h. After standing to cool, with preparative HPLC (10mM NH 4 HCO 3 +NH 3 (pH=9.2)=90:10 to 20:80) directly purify the reaction solution. The active fraction was concentrated and dried to give 3-(4-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)-N-methyl-1,2,4-oxadiazole - 5-Carboxylate (23 mg) as a solid.

[0177] According to a method similar to the method described in Example 2 using the corresponding starting compounds, the compounds in Preparation Examples 2-1 to 2-26 shown in the table below were prepared.

[0178] Table 4

[0179]

[0180] Table 4 (continued)

[0181]

[0182] Table 4 (continued)

[0183]

[0184] table 5

[0185]

preparation example 3

[0187]Benzyl 4-chloro-1H-pyrrolo[2,3-b]pyridine-5-carboxylate (55mg), ethyl {[(4-amino-1-adamantyl)carbonyl]amino}acetate (54mg ) and triethylamine (80 μl) were dissolved in N-methyl-2-pyrrolidone (0.55 ml), and stirred at 180° C. for 1 hour using a microwave reaction system. Ethyl acetate and water were added to the resulting reaction liquid, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate), the obtained compound was dissolved in dioxane (1.1ml) and methanol (1.1ml), and 10% palladium-carbon (50% wet), and the catalytic reduction reaction was carried out at ambient temperature and 1 atmospheric pressure for 4 hours. Methanol, dioxane, and 1M hydrochloric acid were added, and the precipitated solid was dissolved and filtered to remove the catalyst. The filtrate was conce...

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PUM

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Abstract

The present invention provides a compound of formula (I) having an excellent JAK3 inhibition activity and being useful as an active ingredient of an agent for treating and / or preventing various immune diseases including autoimmune diseases inflammatory diseases, and allergic diseases. The compound according to the present invention has an inhibition activity against JAK3 and is thus useful as an active ingredient of an agent for treating or preventing diseases caused by undesirable cytokine signal transmission (e.g., rejection during organ / tissue transplantation, autoimmune diseases, multiple sclerosis, rheumatoid arthritis, psoriasis, asthma, atopic dermatitis, Alzheimer's disease, and atherosclerotic disease), or diseases caused by abnormal cytokine signal transmission (e.g., cancer and leukemia).

Description

technical field [0001] The present invention relates to a novel condensed heterocyclic compound and a drug containing the compound as an active ingredient. Specifically, the present invention relates to a therapeutic agent for immune diseases. Background technique [0002] Janus kinase 3 (hereinafter referred to as JAK3) is a member of the protein kinase family. Although other kinases in this family besides JAK3 are expressed in many tissues, JAK3 is only expressed in hematopoietic cells. This is consistent with the important role of JAK3 in signaling through various receptors such as interleukin (hereinafter referred to as IL)-2, IL-4, IL-7, IL-9, IL-15 and IL-21 , the signal transduction process is carried out through the non-covalent combination of the above-mentioned receptors and the common γ chain (see Non-Patent Document 1 and Non-Patent Document 2). [0003] It has been found that the amount of JAK3 protein is reduced in the XSCID (X-linked severe combined immunode...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D471/04C07D471/14A61P37/06A61P11/06A61P17/00A61P25/28A61P35/00A61P35/02A61K31/437C07D451/04
CPCC07D519/00C07D471/04C07D451/04C07D471/14A61P11/00A61P11/06A61P17/00A61P17/06A61P19/02A61P25/00A61P25/28A61P29/00A61P35/00A61P35/02A61P37/00A61P37/06A61P37/08A61P43/00A61K31/437
Inventor 井上隆幸田中明中井一夫佐佐木弘高桥史江白神升平畑中惠子中岛丰向吉耕一朗滨口寿雄国川茂辉东康之
Owner ASTELLAS PHARMA INC
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