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Novel dicarboxylic acid derivatives

A compound, alkyl technology, applied in the field of new dicarboxylic acid derivatives, can solve problems such as lack of selectivity

Inactive Publication Date: 2008-01-16
BIOPROJET +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0009] However, FTY720 and its homologues have two potential drawbacks, namely: they need to be phosphorylated in vivo for activation (Brinkmann et al., J.Biol.Chem., 277, 24, pp. 21453-21457, 2002) and have a negative effect on The five S1P receptor subclasses lack selectivity (Mandala et al., Science, 296, pp. 346-349, 2002)

Method used

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Examples

Experimental program
Comparison scheme
Effect test

preparation example Construction

[0398] Preparation of C 4-nonylbenzylamine

[0399] Step I

[0400] synthetic route:

[0401]

[0402] Triethylsilane (20 mL) was added dropwise to a stirred solution of 1-(4-bromophenyl)nonan-1-one (10 g, 0.033 mol) in TFA (20 mL) at room temperature. The mixture was then heated to reflux for 4.5 h. The reaction mixture was cooled and concentrated under reduced pressure. The resulting residue was purified by column chromatography (silica gel 230-400 mesh, n-hexane:ethyl acetate; 95:5) to obtain 1-bromo-4-nonylbenzene.

[0403] Reference: J. Org. Chem. 38, 2675 (1973)

[0404] Step II

[0405] synthetic route:

[0406]

[0407] A small amount of iodine crystals was added to a heterogeneous solution of magnesium (0.771 g, 0.032 mol) in THF (10 mL) under a nitrogen atmosphere, followed by 5 mL of 1-bromo in THF (40 mL) at 650 C under vigorous stirring - 4-Nonylbenzene (6.5 g, 0.0229 mol). After starting, the remaining 1-bromo-4-nonylbenzene solution was added dropw...

Embodiment 1 and 2

[0445] 3-(4-Octylbenzylamino)cyclopentane-1,1-dicarboxylate hydrochloride and 3-(4-octylbenzylamino)cyclopentane-1,1-dicarboxylic acid ethyl ester

[0446] A solution of diethyl 3-oxocyclopentane-1,1-dicarboxylate (0.55 g, 0.00241 mol) in dichloromethane (5 mL) was added to stirred 4-octylbenzylamine ( 0.53 g, 0.00242 mol) in a solution in dichloromethane (20 mL) and methanol (2 mL). The reaction mixture was cooled to 5 to 100C and sodium cyanoborohydride (0.530 g, 0.0084 mol) was added. The reaction mixture was allowed to come to room temperature and stirred at room temperature for 4 h. The reaction mixture was concentrated under reduced pressure, and the residue was quenched with water (10 mL). Extracted in ethyl acetate (2 x 20 mL). The combined organic layers were washed with brine (1 x 10 mL) and dried over sodium sulfate. The solvent was removed to obtain a viscous liquid, which was purified by column chromatography (silica gel 230-400 mesh, mobile phase n-hexane:et...

Embodiment 3

[0454] Example 3 as hydrochloride

[0455] 13 C NMR: (CDCl3+TFA; 100.61MHz; ppm)

[0456] 14.66(q);23.32(t);29.48(t);29.97(t);29.98(t);30.10(t);30.18(t);31.86(t);32.55(t);33.59(t); 36.29(t);37.40(t);51.77(t);58.54(d);59.82(s);126.78(s);130.19(2d);130.28(2d);146.54(s);175.62(s); 176.89(s)

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Abstract

The present patent application concerns new compounds of formula (I): displaying agonistic activity at sphingosine-1-phosphate (S1P) receptors, their process of preparation and their use as immunosuppressive agents.

Description

technical field [0001] This patent application relates to novel compounds exhibiting agonistic activity at the sphingosine-1-phosphate (S1P) receptor, their preparation and their use as immunosuppressants. Background technique [0002] Among other actions, indirect or direct S1P receptor agonists inhibit thymic egress and lymphocyte recirculation (Rosen et al., Immunol. Rev. 2003, 195, 160). [0003] Inhibition of lymphocyte efflux is clinically relevant for immunosuppression in transplantation and autoimmune diseases. [0004] Agonism of sphingosine-1-phosphate receptors (especially S1P1 receptors) results in accelerated lymphocyte homing to lymph nodes and Peyer's patches without lymphocyte depletion. Such immunosuppressive effects are expected to prevent rejection after organ transplantation and in the treatment of autoimmune diseases. [0005] Immunosuppressants have been shown to be useful in a variety of autoimmune and chronic inflammatory diseases, including transpl...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C229/30C07C229/48C07C237/24C07C323/12A61K31/10A61K31/165A61K31/196A61K31/197A61K31/216A61P37/06
CPCC07C229/48C07C229/30C07C2101/08C07C323/12C07C237/24C07C2601/08A61P1/04A61P11/00A61P11/06A61P13/12A61P17/00A61P17/06A61P19/02A61P25/00A61P29/00A61P3/10A61P31/04A61P35/00A61P35/02A61P37/00A61P37/02A61P37/06A61P37/08A61P43/00A61P7/00A61P9/04A61P9/10A61K31/10
Inventor 马克·卡佩尼古拉斯·勒瓦伊莎贝尔·贝雷比-贝特朗奥利维娅·普帕尔丹菲利普·罗伯特让-查尔斯·施瓦茨让娜-马里·勒孔特泰那提·拉贾马纳尔兰詹·库马尔·帕尔比斯瓦吉特·萨曼塔日格内什·K·吉瓦尼巴韦什·M·潘沙尔伊沙·H·巴特杰拉杰·D·阿拉德海耶
Owner BIOPROJET
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