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Novel aminopyridine compounds having Syk inhibitory activity

A technology of aminopyridine and compounds, which is applied in the field of therapeutic drugs for allergic diseases and aminopyridine compounds, and can solve the problems of low specificity and immunosuppression

Inactive Publication Date: 2008-04-23
JAPAN TOBACCO INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0076] Syk inhibitors reported so far show inhibitory effects on various protein kinases due to their low specificity (selectivity), so they not only suppress inflammatory reactions, but also may cause immunosuppressive effects

Method used

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  • Novel aminopyridine compounds having Syk inhibitory activity
  • Novel aminopyridine compounds having Syk inhibitory activity
  • Novel aminopyridine compounds having Syk inhibitory activity

Examples

Experimental program
Comparison scheme
Effect test

manufacture example 1

[1887] Manufacturing Example 1: (Process Diagram 1)

[1888]

[1889] (X represents a leaving group such as a halogen atom, and R 7 ' means R 7 Nucleophilic substituents. The other symbols have the same meanings as described above. )

[1890] first process

[1891] Compound (2) is halogenated in a solvent such as dichloromethane, 1,2-dichloroethane, chloroform, carbon tetrachloride, acetonitrile, toluene, etc., using a halogenating agent such as thionyl chloride, oxalyl chloride, or in three In the presence of bases such as ethylamine, N,N-diisopropylethylamine, and pyridine, the reaction is carried out using a leaving group-introducing reagent such as methanesulfonyl chloride, p-toluenesulfonyl chloride, or trifluoromethanesulfonic anhydride to obtain compound (3).

[1892] second process

[1893] Compound (4) in ethanol, isopropanol, ethyl acetate, tetrahydrofuran, N,N-dimethylformamide, dimethyl sulfoxide, chloroform, acetonitrile, ethylene glycol dimethyl ether...

manufacture example 2

[1898] Manufacturing Example 2: (Process Diagram 2)

[1899] (The symbols in the figure have the same meanings as those described above.)

[1900]

[1901] Fifth process

[1902] By following the method described in Organic Letters, 5(18), 3233-3236, (2003), in solvents such as acetonitrile, tetrahydrofuran, 1,4-dioxane, N,N-dimethylformamide, magnesium chloride In the presence of bases such as triethylamine and N,N-diisopropylethylamine, nicotinic acid chloride compound (8) is reacted with malonic acid compound (9), and then concentrated hydrochloric acid is used for simultaneous decarboxylation and tert-butyl Deprotection of the oxycarbonyl group affords compound (10).

[1903] Sixth process

[1904] By making the compound ( 10) react with compound (11) to obtain compound (12). In this reaction, a base such as pyridine, triethylamine, N,N-diisopropylethylamine or the like may be used depending on the case. When the compound (11) is a carboxylic acid compound, ...

manufacture example 3

[1907] Manufacturing Example 3: (Process Diagram 3)

[1908]

[1909] Eighth process

[1910] Compound (15) can be obtained by reacting compound (7) and compound (14) according to the method shown in the fourth step.

[1911] Ninth process

[1912] In the presence of tetrakis (triphenylphosphine) palladium and sodium bicarbonate, potassium bicarbonate, sodium carbonate, potassium carbonate and other bases, in dimethoxyethane, diethyl ether, acetone, methyl ethyl ketone, Compound [I] can be obtained by reacting compound (15) with compound (16) in a solvent such as dioxane or tetrahydrofuran.

[1913] where the substituent R is required 7 In the case of a compound [I] having a "-CONH-bond", it can be obtained by combining a compound having a "-COOH group" and a compound having a "-NH 2 Compounds with the "group" can undergo amidation reaction to obtain the compound [I] with the desired "-CONH-bond".

[1914] In addition, where the substituent R is required 7 with "-N(-(...

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Abstract

Disclosed is an aminopyridine compound represented by the formula (I) below or a salt thereof. Also disclosed is an Syk inhibitor containing such a compound or salt as an active constituent. In the formula (I) below, X<1>, X<2>, X<3>, Z, Y<1> and Y<2> respectively represent a carbon atom or a nitrogen atom; R, R<1>, R<5> and R<6> respectively represent a hydrogen atom, an alkyl group or the like; and R<7> represents a hydrogen atom, a halogen atom, a nitro group, a cyano group, -CpH2(p1)(R)(R)-O-R, -C(=O)-R, a five-membered or six-membered saturated heterocyclic group, an aromatic heterocyclic group, -N(R )(R ) or the like. The aminopyridine compound has not only high Syk inhibitory activity but also characteristics of selectively inhibiting Syk. C07D 409 / 14 A61K 31 / 4436 A61K 31 / 4439 A61K 31 / 444 A61K 31 / 4545 A61K 31 / 496 A61K 31 / 506 A61K 31 / 5377 A61K 31 / 541 A61P 11 / 06 A61P 17 / 00 A61P 19 / 02 A61P 25 / 00 A61P 27 / 02 A61P 27 / 16 A61P 29 / 00 A61P 35 / 00 A61P 35 / 02 A61P 37 / 02 A61P 37 / 08 A61P 43 / 00 C07D 417 / 14 C07D 413 / 14 0 343 63 2006 / 2 / 24 101166734 2008 / 4 / 23 000000000 Japan Tobacco Inc. Japan Kodama Yoshitoshi Noji Satoru Imamura Katsuaki Mizojiri Ryo Aoki Kenta Takagi Hideo Naka Yuichi Ito Goro Shinoda Kiyotaka Fujiwara Akihito Kurihara Kazunori Tanaka Masaru ligui liang 11021 The Patent Agency of the Chinese Academy of Sciences Inside the Chinese Academy of Sciences, No.52 Sanlihe Road, Fuwai, Beijing 100864 Japan 2005 / 2 / 28 052469 / 2005 United 2005 / 3 / 4 60 / 658,885 Japan 2006 / 1 / 19 011751 / 2006 United 2006 / 1 / 27 60 / 763,045 2007 / 10 / 17 PCT / JP2006 / 304034 2006 / 2 / 24 WO2006 / 093247 2006 / 9 / 8 Japanese

Description

technical field [0001] The present invention relates to a novel aminopyridine compound having a Syk (Spleen tyrosine kinase) inhibitory effect and an allergic disease therapeutic drug containing the compound as an active ingredient. Background technique [0002] 1. What are allergic diseases such as bronchial asthma; [0003] Type I (immediate) allergic reactions, which are known to play an important role in allergic diseases represented by bronchial asthma, allergic rhinitis, and atopic dermatitis, are caused by exogenous antigens such as pollen or house dust and specific antigens for them. It is triggered by the interaction of immunoglobulin E (IgE). Allergens that invade the body are presented to helper T cells (Th cells) by antigen-presenting cells such as macrophages as HLA Class II molecules and peptide fragments. Th cells are activated by antigen stimulation through T cell receptors to produce IL-4 and other cytokines. As a result, the production of IgE antibodies ...

Claims

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Application Information

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IPC IPC(8): C07D409/14A61K31/4436A61K31/4439A61K31/444A61K31/4545A61K31/496A61K31/506A61K31/5377A61K31/541A61P11/06A61P17/00A61P19/02A61P25/00A61P27/02A61P27/16A61P29/00A61P35/00A61P35/02A61P37/02A61P37/08A61P43/00C07D417/14C07D413/14
Inventor 儿玉淑功野路悟今村胜明沟尻亮青木健太高木秀夫仲裕一伊藤吾朗筱田清孝藤原明比等栗原一典田中大
Owner JAPAN TOBACCO INC
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