Hetero compound

A compound, heterocycloalkyl technology, applied in the field of pharmaceuticals, can solve problems such as useless observations

Active Publication Date: 2009-04-22
ASTELLAS PHARMA INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

On the other hand, it was found that S1P 3 Also expressed on cardiomyocytes, due to the stimulation of sphingosine 1-phosphate, a transient reduction in heart rate (bradycardia) and blood pressure was observed (non-patent literature 3), for the S1P 3 Bradycardia induced by sphingosine 1-phosphate stimulation was not observed in genetically deficient knockout mice (Non-Patent Document 4)

Method used

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Examples

Experimental program
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Embodiment

[0176] Hereinafter, the present invention will be described in detail based on examples. The present invention is not limited to the invention of the compounds described in the following examples. In addition, the production method of the raw material compound is shown in the production example.

[0177] [In the following table, Pr represents the production example number, and "Structure" represents the structural formula. The abbreviation Me in the structural formula represents a methyl group, and Et represents an ethyl group. Crossed double bonds indicate a mixture of cis and trans forms, and when only numbers are written in the Data column, MS data are indicated. MS indicates mass analytical data. In the table, what is described as RT indicates the retention time in high performance liquid chromatography (HPLC), and M indicates minutes. The conditions of HPLC are expressed as: [column: Intertsil ODS-3 4.6×150mm, eluent 0.01M KH 2 PO 4 aq. / MeCN (3:7), flow rate: 1.0ml / ...

manufacture example 1

[0179] Imidazo[1,2-a]pyridine-7-carbonitrile hydrochloride (1.50g), hydroxylamine hydrochloride (301mg) and Na 2 CO 3 (3.50g) in CH 3 OH (57ml) was stirred at 60°C for 6 hours. The reaction liquid was cooled and concentrated, and the completion of the reaction was confirmed by LC-MS. Water was added to the residue, and extracted twice with EtOAc. The organic layer was washed with water and saturated brine, and washed with anhydrous MgSO 4 After drying and filtration, the filtrate was concentrated to give N'-hydroxyimidazo[1,2-a]pyridine-7-carboxamide (850 mg) as a white solid.

[0180] The compounds shown by Pr1-1 to Pr1-17 in the table were produced in the same manner as in Production Example 1.

[0181] [table 3]

[0182]

manufacture example 2

[0184] In a 50 ml reaction vessel, hydroxylamine (50% in water) was added to 1H-indole-4-carbonitrile (5.00 g) at room temperature in CH 3 OH (100ml) solution, refluxed for 15 hours (confirmed the completion of the reaction by TLC). The reaction solution was concentrated under reduced pressure and azeotroped with toluene three times. The resulting solid was washed with IPE. N'-Hydroxy-1H-indole-4-carboxyimidazolamide (6.12 g) was obtained in the form of a white solid.

[0185] The compounds shown in Pr2-1 to Pr2-26 in the table were produced in the same manner as in Production Example 2.

[0186] [Table 4]

[0187]

[0188] [table 5]

[0189]

[0190] [Table 6]

[0191] Pr NMR 2-16

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Abstract

It is intended to provide a useful compound as an active ingredient of a preventive and / or therapeutic agent for rejection in the transplantation of an organ, bone marrow, or tissue, an autoimmune disease or the like which has an excellent S1P1 agonist effect. Because the compound of the invention has an S1P1 agonist effect, it is useful as an active ingredient of a therapeutic agent or a preventive agent for a disease caused by unfavorable lymphocytic infiltration, for example, an autoimmune disease such as graft rejection in the transplantation of an organ, bone marrow, or tissue or graft-versus-host disease, rheumatic arthritis, multiple sclerosis, systemic lupus erythematosus, nephrotic syndrome, encephalomeningitis, myasthenia gravis, pancreatitis, hepatitis, nephritis, diabetes, pulmonary disorder, asthma, atopic dermatitis, inflammatory bowel disease, atherosclerosis, or ischemia-reperfusion injury or an inflammatory disease, and further, a disease caused by the abnormal growth or accumulation of cells such as cancer or leukemia.

Description

technical field [0001] The present invention relates to novel heterocyclic compounds (ヘテロ compound) and pharmaceuticals containing them as active ingredients, especially therapeutic agents for immune diseases. Background technique [0002] Sphingosine 1-phosphate is a metabolite of sphingolipid which is a physiologically active substance secreted from activated platelets (Non-Patent Document 1). The receptor of sphingosine 1-phosphate is G protein-binding type, which belongs to the Edg family of endothelial differentiation genes, and S1P has been found so far 1 (Edg1), S1P 2 (Edg5), S1P 3 (Edg3), S1P 4 (Edg6), S1P 5 (Edg8) These 5 receptors. All receptors are widely distributed in cells and tissues throughout the body, but S1P 1 , S1P 3 and S1P 4 Abundantly expressed in lymphocytes and vascular endothelial cells, S1P 2 Abundantly expressed in vascular smooth muscle cells, S1P 5 It is abundantly expressed in the brain and spleen, and these amino acid sequences are w...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D413/04A61K31/4245A61K31/4353A61K31/4709A61P37/02A61P37/06A61P43/00C07D417/04C07D471/04
Inventor 原田博规服部和之藤田和也森田真正今田直阿部义人井谷弘道宝方达昭津津美秀雄
Owner ASTELLAS PHARMA INC
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