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Sphingosine 1-phosphate agonists comprising cycloalkanes and 5-membered heterocycles substitued by amino and phenyl groups

A cycloalkyl, alkyl technology, applied in the field of novel sphingosine-1-phosphate analogues, which can solve problems such as limitations, lack of solubility, and synthetic complexity

Inactive Publication Date: 2008-02-06
UNIV OF VIRGINIA ALUMNI PATENTS FOUND
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Isolation and characterization of S1P analogs with potent agonist or antagonist activity at the S1P receptor is limited due to synthetic complexity resulting from the lack of solubility of S1P analogs

Method used

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  • Sphingosine 1-phosphate agonists comprising cycloalkanes and 5-membered heterocycles substitued by amino and phenyl groups
  • Sphingosine 1-phosphate agonists comprising cycloalkanes and 5-membered heterocycles substitued by amino and phenyl groups
  • Sphingosine 1-phosphate agonists comprising cycloalkanes and 5-membered heterocycles substitued by amino and phenyl groups

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0206] Example 1: (1-amino-3-(4-octylphenyl)cyclopentyl)methanol (6)

[0207] A: 3-(4-iodophenyl)cyclopentanone (1)

[0208] in N 2 0.23 g palladium(II) acetate (0.1 eq) and 0.23 g antimony (III) chloride (0.1 eq) were added to 80 mL containing 0.82 g (10 mmol) 2-cyclopent-1-one, 2.48 g (10 mmol) Acetic acid solution of 4-iodophenylboronic acid and 1.6g (20mmol) sodium acetate. After stirring at 25°C for 24 hours, the black precipitate was removed by filtration and the filtrate was diluted with 250 mL of brine and extracted twice with 50 mL of dichloromethane. Use saturated NaHCO 3 The solution was stirred with the organic extract for 30 min, then washed with brine and washed with MgSO 4 dry. Removal of solvent gave a yellow oil which was further purified using flash column (chloroform) to give 1.92 g (67%) of the product as a white solid. J. Org. Chem., 1995, 60, 883-888.

[0209] 1 H NMR (CDCl 3 )δ7.63 (d, 2H, ArH), 7.00 (d, 2H, ArH), 3.35 (m, 1H, ArCHCC), 2.7-1.8...

Embodiment 2

[0229] Example 2: (1-amino-3-(4-octylphenyl) cyclopentyl) methyl dihydrogen phosphate (7)

[0230] (1-Amino-3-(4-octylphenyl)cyclopentyl)methyl dihydrogen phosphate (7)

[0231] 1 mL of 85% H 3 PO 4 Slowly add 0.5 g of P 2 o 5 , in, and then at N 2 Under protection, the acid-anhydride mixture was heated at 100°C for 1 hour. Add another 0.5g of P 2 o 5 and 30mg of 6 were added to polyphosphoric acid and heated at 100°C for 5 hours. After cooling to room temperature, 10 mL of ice water was added to the reaction mixture. The product precipitated out as a white solid. The product was collected and washed with water. 31 mg (82%) of the green product were collected after vacuum drying. MS only two peaks: M+1 = 384.4 and 304.4 (hydrolyzed back to 6).

Embodiment 3

[0232] Example 3: GTPγS-35 binding assay

[0233] This assay demonstrates agonist activity of G protein-coupled receptors (GPCRs) in isolation. This assay induces recombinant GPCRs (such as S1P1-5 receptors) and three subunits of heterotrimeric G proteins (typically α1, β2, γ3) by transfecting HEK293T cells with four plasmid DNAs encoding each protein Concomitant expression of each in said cells. Approximately 60 hours after transfection, cells were harvested, disrupted, and nuclei discarded. This allows the preparation of coarse microsomes from the residue. Stimulation with agonists (eg, S1P) of the G protein receptor complex on microsomes results in a dose-dependent conversion of GTP to GDP on the alpha subunit. To detect the GTP-bound alpha subunit, a GTP analog (GTPγS-35), a radionuclide (sulfur-35) labeled phosphorothioate that is not hydrolyzed to GDP, was used. Microsomes with attached G protein were collected by filtration and bound GTPγS-35 was quantified in a l...

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Abstract

The present invention provides sphingosine-1-phosphate analogs that are potent, and selective agonists at one or more S1P receptors, specifically the S1P1 receptor type. The compounds invention include compounds having a phosphate moiety as well as compounds with hydrolysis-resistant phosphate surrogates such as phosphonates, alpha-substituted phosphonates, and phosphothionates.

Description

[0001] Cross-references to related applications [0002] This application claims priority to provisional applications 60 / 652,642, filed February 14, 2005 and 60 / 669,616, filed April 8, 2005, and 60 / 692,760, filed June 22, 2005, all of which The content is incorporated by reference into this application in its entirety. [0003] US government rights [0004] This invention was made with US Government support under Grant Nos. RO1 GM067958 and RO1 GM052722 awarded by the National Institutes of Health. The US Government has certain rights in this invention. technical field [0005] The present invention relates to novel sphingosine-1-phosphate analogs that are active at one or more sphingosine-1-phosphate receptors. Background technique [0006] Sphingosine 1-phosphate (S1P) is a lysophospholipid modulator that elicits a variety of cellular responses by stimulating five members of the endothelial differentiation gene (EDG) receptor family. The EDG receptor is a G protein-cou...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/137A61K31/425A61K31/665A61K31/40A61K31/415A61K31/67A61K31/402A61K31/381A61K31/675A61K31/42A61K31/661A61K31/341A61K31/662A61P1/00A61P7/12
Inventor 凯文·R·林奇蒂莫西·L·麦克唐纳
Owner UNIV OF VIRGINIA ALUMNI PATENTS FOUND
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