3,5-aryl, heteroaryl or cycloalkyl substituted-1,2,4-oxadiazoles as S1P receptor agonists

A cycloalkyl compound technology, applied in the field of 3,5-aryl, heteroaryl or cycloalkyl-substituted 1,2,4-oxadiazole compounds as S1P receptor agonists, capable of Work around limitations, etc.

Inactive Publication Date: 2006-11-08
MERCK & CO INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, sphingosine 1-phosphate also has some cardiovascular and bronchoconstrictive effects that limit its utility as a therapeutic agent

Method used

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  • 3,5-aryl, heteroaryl or cycloalkyl substituted-1,2,4-oxadiazoles as S1P receptor agonists
  • 3,5-aryl, heteroaryl or cycloalkyl substituted-1,2,4-oxadiazoles as S1P receptor agonists
  • 3,5-aryl, heteroaryl or cycloalkyl substituted-1,2,4-oxadiazoles as S1P receptor agonists

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0267] 3-(2-Methyl-5-chlorophenyl)-5-(4-(2-methylpropyl)phenyl)-1,2,4-oxadiazole

[0268] Step A: N-Hydroxy-(2-methyl-5-chloro)benzamidine

[0269] A mixture of 2.50 g (16.5 mmol) 5-chloro-2-methylbenzonitrile, 2.30 g (33 mmol) hydroxylamine hydrochloride and 6.90 g (82.5 mmol) sodium bicarbonate in 25 mL MeOH methanol was stirred at 50° C. for 16 h. The reaction mixture was cooled, diluted with 50 mL 2N HCl, then washed with 3 x 30 mL CH 2 Cl 2 and 1 x 30 mL EtOAc for extraction. The combined organics were dried and concentrated to give 2.15 g of the title compound:

[0270] 1 H NMR (500MHz, CD 3 OD): δ7.29-7.34 (m, 2H), 7.23 (d, J=8.0, 1H), 2.38 (s, 3H). Step B: 3-(2-methyl-5-chlorophenyl)- 5-(4-(2-methylpropyl)phenyl)-1,2,4-oxadiazole

[0271] 500mg (2.8mmol) 4-(2-methylpropyl) benzoic acid, 600mg (3.1mmol) hydrochloride 1-(3-(dimethylamino)propyl)-3-ethylcarbodiimide and 420mg A mixture of (3.1 mmol) 1-hydroxybenzotriazole in 10 mL of acetonitrile was stirred at rt...

Embodiment 2-18

[0274] The following compounds were prepared using methods similar to those described in Example 1, substituting the appropriate carboxylic acid for 4-(2-methylpropyl)benzoic acid in Step B.

[0275]

[0276]

[0277]

[0278]

[0279]

Embodiment 19-25

[0281] The following compounds were prepared in a manner similar to those described in Example 1, substituting the appropriate nitrile for (2-methyl-5-chloro)benzonitrile in Step A and 4-(cyclohexyl) Benzoic acid was substituted for 4-(2-methylpropyl)benzoic acid.

[0282]

[0283]

[0284]

[0285]

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PUM

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Abstract

The present invention encompasses compounds of Formula I: (I) as well as the pharmaceutically acceptable salts thereof. The compounds are useful for treating immune mediated diseases and conditions, such as bone marrow, organ and tissue transplant rejection. Pharmaceutical compositions and methods of use are included.

Description

technical field [0001] The present invention relates to S1P 1 / Edg1 receptor agonists and thus compounds that are immunologically active by modulating leukocyte flux, sequestering lymphocytes in secondary lymphoid tissues, and interfering with cell:cell interactions required in an effective immune response. The present invention also relates to pharmaceutical compositions containing such compounds and some methods of treatment or prevention. Background technique [0002] Immunosuppressants have been shown to be useful in many autoimmune and chronic inflammatory diseases, including systemic lupus erythematosis, chronic rheumatoid arthritis, type I diabetes, inflammatory bowel disease, biliary cirrhosis, uveal 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. It has also been shown to be...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/4245A61KC07D271/06
CPCA61P1/00A61P1/02A61P3/10A61P11/00A61P11/06A61P17/00A61P17/06A61P25/28A61P27/02A61P29/00A61P31/04A61P31/12A61P35/00A61P35/02A61P37/00A61P37/02C07D271/06C07D413/04
Inventor G·A·多赫尔蒂J·J·哈尔I·E·莱吉克C·L·林奇L·M·托思
Owner MERCK & CO INC
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