(3,4-disubstituted)propanoic carboxylates as SLP (EDG) receptor agonists

一种取代基、烷基的技术，应用在作为鞘氨醇1－磷酸(内皮分化基因)受体激动剂的(3,4－二取代)丙酸酯领域，能够解决限制用途等问题

Inactive Publication Date: 2007-01-10
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 cardiovascular and bronchoconstrictive effects, which limit its usefulness as a therapeutic drug

Method used

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  • (3,4-disubstituted)propanoic carboxylates as SLP (EDG) receptor agonists
  • (3,4-disubstituted)propanoic carboxylates as SLP (EDG) receptor agonists
  • (3,4-disubstituted)propanoic carboxylates as SLP (EDG) receptor agonists

Examples

Experimental program
Comparison scheme
Effect test

preparation example Construction

[0226] Preparation of N-hydroxyamidine intermediate

[0227] N-hydroxyamidine 1

[0228] N-Hydroxy 3-methyl-4-(2-(tert-butoxycarbonyl)ethyl)benzamidine

[0229] Step A: tert-butyl 3-(3-methyl-4-cyanophenyl)acrylate

[0230] 10.0g (51.0mmol) of 4-bromo-2-methylbenzonitrile in 80ml 1,4-two-alkanes solution with 7.19g (56.1mmol) tert-butyl acrylate, 10.96g (56.1mol) N-methyl di Treat with cyclohexylamine, 228 mg (0.76 mol) 2-(di-tert-butylphosphino)biphenyl and 396 mg (0.38 mol) tris(dibenzylideneacetone)dipalladium(0)-chloroform adduct. The resulting mixture was heated at 70°C for 16 hours and cooled to room temperature. The reaction mixture was filtered through filter paper, and the filtrate was concentrated. The crude product was divided into four fractions. Chromatography (4 Biotage 40M columns, 19:1 v / v Hexane / EtOAc as eluent) followed by pooling of product fractions afforded 10.0 g of the title compound:

[0231] 1 H NMR (500MHz, CDC...

Embodiment 1

[0443] 3-(4-(5-(3-cyano-4-isopropoxyphenyl)-1,2,4-oxadiazol-3-yl)-3-methylphenyl)propanoic acid

[0444] Step A: 3-(4-(5-(3-cyano-4-isopropoxyphenyl)-1,2,4-oxadiazol-3-yl)-3-methylphenyl)propane tert-butyl acid

[0445] 25mg (0.09mmol) N-hydroxyamidine 1, 21mg (0.10mmol) carboxylic acid 1, 26mg (0.14mmol) N-(3-dimethylamino-propyl)-N'-ethylcarbodiimide and 5ml The mixture of acetonitrile was stirred at room temperature for 2 hours and then at 120°C for 16 hours. The reaction mixture was cooled to room temperature and concentrated. Column chromatography on a Biotage 40S (17:3 v / v hexane / EtOAc as eluent) afforded 23 mg of the title compound: 1 H NMR (500MHz, CDCl 3 )δ 1.43(s, 9H), 1.47(d, J=6.2, 6H), 2.57(t, J=7.7, 2H), 2.65(s, 3H), 2.95(t, J=7.7, 2H), 4.76-4.83 (m, 1H), 7.11 (d, J=8.9, 1H), 7.17-7.19 (m, 2H), 7.99 (d, J=8.2, 1H), 8.33 (dd, J=2.3, 9.0, 1H), 8.42 (d, J=2.0, 1H).

[0446] Step B: 3-(4-(5-(3-cyano-4-isopropoxyphenyl)-1,2,4-oxadiazol-3-yl)-3-methylphenyl)prop...

Embodiment 2-7

[0450] The following examples were prepared in a manner similar to that described in Example 1, substituting the appropriate carboxylic acid for carboxylic acid 1 in Step A.

[0451]

[0452]

[0453]

[0454] 1 H NMR (500MHz, CD 3 OD) δ1.40(d, J=5.9, 6H), 2.61(s, 3H), 2.66(t, J=7.8, 2H).2.96

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Abstract

The present invention encompasses compounds of Formula A: A as well as the pharmaceutically acceptable salts thereof. The compounds are S1P1 / Edg1 receptor agonists and thus have immunosuppressive, anti-inflammatory and hemostatic activities by modulating leukocyte trafficking, sequestering lymphocytes in secondary lymphoid tissues, and enhancing vascular integrity. The invention is also directed to pharmaceutical compositions containing such compounds and methods of treatment or prevention.

Description

Background of the invention [0001] The present invention relates to S1P 1 / Edg1 receptor agonists, these compounds can regulate leukocyte trafficking, recruit lymphocytes in secondary lymphoid tissues, and improve vascular integrity, and thus have immunosuppressive activity, anti-inflammatory activity and hemostatic activity. The invention also relates to pharmaceutical compositions comprising such compounds and methods of treatment or prophylaxis. [0002] Immunosuppressive and anti-inflammatory drugs have been shown to be useful in many autoimmune and chronic inflammatory diseases (including systemic lupus erythematosus, chronic rheumatoid arthritis, type 1 diabetes, inflammatory bowel disease, biliary cirrhosis, grapevine meningitis, multiple sclerosis, and other diseases such as Crohn's disease, ulcerative colitis, bullous pemphigoid, sarcoidosis, psoriasis, autoimmune myositis, Wegener's granulomatosis, ichthyosis, Graves ophthalmopathy, atopic dermatitis and asthma), c...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D271/06C07D413/04C07D413/14A61K31/4245A61K31/427A61K31/443A61K31/506C07D285/12C07D413/10C07D417/04
CPCC07D413/10C07D413/04C07D271/06C07D417/04C07D413/14A61K31/506C07D285/12A61K31/427A61K31/4245A61K31/443A61P1/02A61P1/04A61P1/16A61P11/00A61P11/02A61P11/06A61P13/12A61P17/00A61P17/06A61P17/14A61P19/10A61P21/00A61P21/04A61P25/00A61P25/06A61P25/28A61P27/12A61P29/00A61P31/14A61P31/20A61P35/00A61P37/02A61P37/06A61P37/08A61P7/00A61P7/06A61P9/00A61P9/04A61P3/10
Inventor V·J·科兰德里G·A·多赫尔蒂J·J·哈尔霍培I·E·勒吉克L·托思P·瓦查尔严林
Owner MERCK & CO INC
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