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Bicyclic aryl sphingosine 1-phosphate analogs

A heteroaryl, A1-A6 technology, applied in the field of bicyclic aryl sphingosine 1-phosphate analogs, can solve the problem of increasing cell migration

Active Publication Date: 2012-07-04
BIOGEN MA INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Ultimately, this S1P-driven signaling leads to cell survival, increased cell migration and often mitosis

Method used

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  • Bicyclic aryl sphingosine 1-phosphate analogs
  • Bicyclic aryl sphingosine 1-phosphate analogs
  • Bicyclic aryl sphingosine 1-phosphate analogs

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0164] Example 1: cis-4-tert-butylcyclohexyl methanesulfonate

[0165]

[0166] Cis-4-t-butylcyclohexanol (6.0 g, 38.5 mmol, 1.0 eq.) was dissolved in dichloromethane (10 mL). Then methanesulfonic anhydride (8.03 g, 46.2 mmol, 1.1 eq.) was slowly added to the mixture at 0 °C. Then triethylamine (6.4 mL, 46.2 mmol, 1.5 eq.) was added to the mixture, and the mixture was stirred at room temperature for 3 h. The mixture was extracted with dichloromethane, and then the organic layer was concentrated to obtain a white powder of the product (8.0 g, yield: 90%). The product was used in the next step without further purification. 1 HNMR (400MHz, CDCl 3 ) δ 4.99-4.98 (m, 1H), 3.02 (s, 3H), 2.14-2.12 (m, 2H), 1.65-1.28 (m, 7H), 0.84 (s, 9H).

Embodiment 2

[0167] Example 2: 2-bromo-6-(trans-4-tert-butylcyclohexyloxy)naphthalene

[0168]

[0169] 6-bromonaphthalen-2-ol (CAS no. 15231-91-1) (3.0 g, 14.8 mmol, 1.0 eq.) was dissolved in a mixture of t-butanol / 2-butanone (4 mL / 2 mL). Cesium carbonate (12 g, 37.2 mmol, 2.5 eq.) was then added to the mixture, and the mixture was stirred at 110° C. for 10 min. Then trans-4-tert-butylcyclohexyl methanesulfonate (3.48 g, 16.2 mmol, 1.1 eq.) was added to the mixture. The suspension was stirred at 110 °C for 15 h under nitrogen atmosphere. The reaction mixture was extracted with ethyl acetate, and the organic layer was purified by silica gel column chromatography using petroleum ether as an eluent to give 2-bromo-6-(trans-4-tert-butylcyclohexyloxy)naphthalene (1.7 g, yield: 32%). ESI-MS: 361.0 (M+H) + . 1 HNMR (400MHz, CDCl 3 )δ7.89(s, 1H), 7.63(d, 1H), 7.56(d, 1H), 7.47(d, 1H), 7.15-7.11(m, 2H), 4.26-4.24(m, 1H), 2.27 -2.25 (m, 2H), 1.89-1.87 (m, 2H), 1.45-1.09 (m, 5H), 0.89 (s, ...

Embodiment 3

[0170] Example 3: 6-(trans-4-tert-butylcyclohexyloxy)-2-naphthaldehyde

[0171]

[0172] 2-Bromo-6-(trans-4-tert-butylcyclohexyloxy)naphthalene (2.249 g, 6.25 mmol, 1.0 eq.) was dissolved in THF (10 mL) under nitrogen atmosphere. The mixture was then cooled to -78 °C, and a solution of n-BuLi in THF (2.5M, 7.5 mL, 18.8 mmol, 3.0 eq.) was added dropwise to the mixture. The mixture was stirred at -78°C for 15 min. Then DMF (2.4 mL, 31.2 mmol, 5.0 eq.) was added to the mixture and stirred at -78 °C for 1 h. When the reaction was complete, 1M HCl was added to adjust the pH to 6. The mixture was extracted with EtOAc, then the organic layer was concentrated and purified by silica gel chromatography using petroleum ether / ethyl acetate (10 / 1) as eluent to give 6-(trans-4-tert Butylcyclohexyloxy)-2-naphthaldehyde as a white solid (1.16 g, 60%). EDI-MS: 311.1(M+H) + . 1 H NMR (400MHz, CDCl 3 )δ10.08(s, 1H), 8.24(s, 1H), 7.92-7.87(m, 2H), 7.77(d, 1H), 7.22-7.19(m, 2H), 4.42-4.3...

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Abstract

Compounds that have agonist activity at one or more of the SlP receptors are provided. The compounds are sphingosine analogs that, after phosphorylation, can behave as agonists at SlP receptors.

Description

Background technique [0001] Sphingosine 1-phosphate (S1P) is a lysophospholipid mediator that induces a variety of cellular responses by stimulating five members of the endothelial differentiation gene (EDG) receptor family. EDG receptors are G-protein-coupled receptors (GPCRs) and, upon stimulation, activate heterotrimeric G-protein α (G α ) subunit and β-γ (G βγ ) dimers to transmit second messenger signals. Ultimately, this S1P-driven signaling leads to cell survival, increased cell migration and often mitosis. Recent advances in agonists targeting the S1P receptor have provided an understanding of the role of this signaling system in physiological homeostasis. For example, the immunomodulator FTY720 (2-amino-2-[2-(4-octylphenyl)ethyl]propane 1,3-diol) is an agonist of 4 out of 5 S1P receptors after phosphorylation agent and has been shown to affect S1P receptor activity affecting lymphocyte trafficking. Moreover, the S1P type 1 receptor (S1P 1 ) antagonists lead to l...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A01N43/42
CPCA61K31/11A61K31/47C07D401/06A61K31/472A61K31/662A61K31/683C07F7/081A61K31/404C07D403/06A61K31/517C07F9/4006C07C2101/02A61K31/216A61K31/18A61K31/337C07C43/247A61K31/695C07D277/64C07D215/20C07D211/62A61K31/41C07C255/54C07D417/06C07D305/08C07D209/08C07D211/60C07D207/16C07C229/14C07C2101/14C07C237/52A61K31/428C07C229/22C07C311/51C07F9/3808C07D217/24C07D205/04C07D215/227C07C2101/16C07C47/575C07C237/08C07D257/04C07F9/3834A61K31/4709C07C2101/08C07C309/14A61K31/197A61K31/445A61K31/085A61K31/397C07C2101/04A61K45/06C07C229/48C07C229/46C07D217/04A61K31/277C07D239/74A61K31/40C07F9/5728C07C2601/02C07C2601/04C07C2601/08C07C2601/14C07C2601/16A61K31/137A61K31/165A61K31/185A61K31/198A61K31/222A61K31/223A61K31/235A61K31/401A61P1/00A61P1/04A61P11/00A61P11/06A61P11/08A61P17/06A61P19/02A61P25/00A61P25/02A61P25/04A61P25/28A61P27/02A61P29/00A61P3/00A61P31/12A61P35/00A61P35/04A61P37/00A61P37/02A61P37/04A61P37/06A61P43/00A61P5/48A61P9/00A61P9/10A61P9/14A61P3/10
Inventor J.托马斯刘晓高林盈翔郑国柱马斌R.D.考德威尔K.M.古基安G.库马拉维尔A.G.塔弗拉斯
Owner BIOGEN MA INC
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