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3-(2-amino-1-azacyclyl)-5-aryl-1,2,4-oxadiazoles as S1P receptor agonists

An alkyl, methyl technology, applied in the field of 3-(2-amino-1-azacyclyl)-5-aryl-1,2,4-oxadiazole as an S1P receptor agonist, Ability to resolve issues such as restricted use

Inactive Publication Date: 2006-06-14
MERCK & CO INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the sphingosine 1-phosphate receptor also has cardiovascular and bronchial effects, which limit its use as a therapeutic agent

Method used

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  • 3-(2-amino-1-azacyclyl)-5-aryl-1,2,4-oxadiazoles as S1P receptor agonists
  • 3-(2-amino-1-azacyclyl)-5-aryl-1,2,4-oxadiazoles as S1P receptor agonists
  • 3-(2-amino-1-azacyclyl)-5-aryl-1,2,4-oxadiazoles as S1P receptor agonists

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0412] 3-(2-(N-methylamino)pyridin-3-yl)-5-((2-methylpropyl)phenyl)-1,2,4-oxadiazole

[0413] Step A: 3-(2-(Chloro)pyridin-3-yl)-5-(4-(2-methylpropyl)phenyl)-1,2,4-oxadiazole

[0414] 500mg (2.8mmol) 4-(2-methylpropyl) benzoic acid, 600mg (3.1mmol) 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride and a mixture of 420 mg (3.1 mmol) 1-hydroxybenzotriazole (0.42 g, 3.09 mmol) in 10 mL DMF was stirred at room temperature for 10 minutes. N-Hydroxyamidine 1 (620 mg, 3.6 mmol) was added and the resulting mixture was heated at 20°C for 3 hours. The reaction was cooled and concentrated. Purification by silica gel chromatography using 3:1 v / v hexane / EtOAc as eluent afforded 103 mg of the title compound:

[0415] 1 H NMR (500MHz, CDCl 3 )δ8.56 (dd, J=2.0, 4.8, 1H), 8.38 (dd, J=2.1, 7.6, 1H), 8.12 (d, J=8.2, 2H), 7.42 (dd, J=4.8, 7.6, 1H), 7.35(d, J=8.2, 2H), 2.59(d, J=7.1, 2H), 1.94(m, 1H), 0.94(d, J=6.7, 6H); ESI-MS 314.1(M+ H).

[0416] Step B: 3-(2-(N-Methylamino)...

Embodiment 2-9

[0420] The following compounds were followed in a manner similar to that described in Example 1, but using 4-(cyclohexyl)benzoic acid in Step A instead of 4-(2-methylpropyl)benzoic acid and the appropriate N-hydroxyamidine N-Hydroxyamidine 1, prepared in Step B by substituting the appropriate amine for N-methylformamide.

[0421]

[0422]

[0423]

Embodiment 10-13

[0425] The following compounds were followed in a manner similar to that described in Example 1, but in Step A the appropriate carboxylic acid was used instead of 4-(2-methylpropyl)benzoic acid and N-hydroxyamidine 3 was used instead of N-hydroxyamidine 1 And made.

[0426]

[0427]

[0428]

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PUM

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Abstract

The present invention includes compounds of formula (I) and pharmaceutically acceptable salts thereof. The compounds are useful in the treatment of immune-mediated diseases and disorders, such as bone marrow, organ and tissue transplant rejection. The invention also includes pharmaceutical compositions and methods of use.

Description

Background of the invention [0001] The present invention relates to as S1P 1 / Edg1 receptor agonist compounds that have immunosuppressive activity by modulating leukocyte trafficking, sequestering lymphocytes in secondary lymphoid tissues, and interfering with cell:cell interactions required for an effective immune response. The invention also relates to pharmaceutical compositions comprising said compounds and methods of treatment or prevention. [0002] Immunosuppressants have been shown to be useful in a variety of autoimmune and chronic inflammatory diseases, including systemic lupus erythematosus, chronic rheumatoid arthritis, type I diabetes, inflammatory bowel disease, biliary cirrhosis, uveitis, Multiple sclerosis and other conditions such as Crohn's disease, ulcerative colitis, bullous pemphigoid, sarcoidosis, psoriasis, autoimmune myositis, Wegener's granulomatosis, ichthyosis, Graves Eye disease, atopic dermatitis and asthma. They have been shown to be used as pa...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D413/04A61K
CPCC07D271/06C07D413/04C07D413/14A61P1/04A61P1/18A61P11/00A61P11/06A61P17/00A61P17/02A61P17/06A61P17/14A61P19/02A61P19/10A61P21/00A61P25/28A61P27/12A61P29/00A61P31/00A61P31/04A61P31/14A61P31/18A61P31/20A61P35/00A61P3/06A61P37/02A61P37/06A61P37/08A61P43/00A61P7/06A61P9/00A61P9/04A61P9/10A61P3/10
Inventor V·J·科兰德里G·A·多赫尔蒂J·J·哈尔C·林奇S·G·米尔斯W·E·纽维三世L·托思
Owner MERCK & CO INC