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Atx modulating agents

A kind of alkyl, independent technology, application in the field of ATX modulator

Inactive Publication Date: 2015-07-08
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, this approach usually only delays rather than prevents the onset of disability in these patients

Method used

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  • Atx modulating agents
  • Atx modulating agents
  • Atx modulating agents

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0691] Example 1: 4-((7-((cis-4-methylcyclohexyl)oxy)-8-(trifluoromethyl)naphthalen-2-yl)methyl)morpholine

[0692]

[0693] Step 1: 2-Bromo-7-(cis-4-methyl-cyclohexyloxy)-naphthalene

[0694]

[0695] To a mixture of 2-bromo-7-hydroxynaphthalene (1.2 g, 0.0053 mol) and cesium carbonate (3.440 g, 0.01056 mol) in N,N-dimethylformamide (10 mL, 0.1 mol) was added in two portions cis-4-methyl-cyclohexyl methanesulfonate (2 g, 0.01 mol). The resulting mixture was heated at 85 °C overnight, and cooled to room temperature, and washed with Et 2 O diluted, washed with water, brine and washed with Na 2 SO 4 dry. The crude mixture was then purified by silica gel (EtOAc / heptane gradient, 0% to 30%) to give the product 2-bromo-7-(cis-4-methyl-cyclohexyloxy)-naphthalene as a solid (778 mg, 46%). LCMS RT = 2.53 min, m / z = 319.10 [M+]. 1H NMR (400MHz, chloroform-d) δ7.86(s, 1H), 7.71(d, J=8.97Hz, 1H), 7.62(d, J=8.66Hz, 1H), 7.38(d, J=8.66Hz ,1H),7.17(d,J=8.85Hz,1H),7.06(s,1H),4...

Embodiment 2

[0714] Example 2: 9-[7-(cis-4-methyl-cyclohexyloxy)-8-trifluoromethyl-naphthalen-2-ylmethyl]-9-aza-bicyclo[3.3.1] Nonane-3-carboxylic acid

[0715]

[0716] 7-(cis-4-methyl-cyclohexyloxy)-8-trifluoromethyl-naphthalen-2-ylmethyl methanesulfonate (105mg, 0.252mmol) in N,N-dimethylformamide (2.9 mL, 38 mmol) was added methyl 9-aza-bicyclo[3.3.1]nonane-3-carboxylate HCl salt (110.79 mg, 0.50426 mmol) followed by cesium carbonate (246.44 mg, 0.75638 mmol). The reaction was then heated at 80°C for 1 hour. LCMS showed no SM remaining and the reaction was complete (RT 1.60 min; MH+504.3). After cooling, the reaction mixture was diluted with EtOAc and washed with water (2x). The organic phase is then separated, dried and concentrated. The crude material was purified by HPLC, the solvent was removed, and the ester was dissolved in tetrahydrofuran (1.2 mL, 14 mmol) and treated with 1.0 M lithium hydroxide in water (1.8 mL, 1.8 mmol) overnight at room temperature. Acidified with ...

Embodiment 3

[0717] Example 3: 8-[7-(cis-4-methyl-cyclohexyloxy)-8-trifluoromethyl-naphthalen-2-ylmethyl]-8-aza-bicyclo[3.2.1] Octane-3-carboxylic acid

[0718]

[0719] 7-(cis-4-methyl-cyclohexyloxy)-8-trifluoromethyl-naphthalen-2-ylmethyl methanesulfonate (105mg, 0.252mmol) in N,N-dimethylformamide 8-Aza-bicyclo[3.2.1]octane-3-carboxylic acid methyl ester HCl salt (103.72mg, 0.50426mmol) and cesium carbonate (246.44mg, 0.75638mmol) were added sequentially to a solution in (2.9mL, 38mmol) . The reaction was then heated at 80°C for 1 hour. LCMS showed no SM remaining and the reaction was complete (RT 1.56 min; MH+ 490.3 and 1.49 min, 476.30). After cooling, the reaction mixture was diluted with EtOAc and washed with water (2x). The organic phase is then separated, dried and concentrated. The crude material was purified by HPLC, the solvent was removed, and the ester was dissolved in tetrahydrofuran (1.2 mL, 14 mmol) and treated with 1.0 M lithium hydroxide in water (1.8 mL, 1.8 mmo...

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Abstract

Disclosed are bicyclic aryl compounds of formula (I), that can modulate the activity of the autotaxin (ATX) enzyme. This invention further relates to compounds that are ATX inhibitors, and methods of making and using such compounds in the treatment of demyelination due to injury or disease, as well as for treating proliferative disorders such as cancer.

Description

[0001] priority claim [0002] This application claims priority to US Provisional Application No. 61 / 676,705, filed July 27, 2012, which is hereby incorporated by reference in its entirety. technical field [0003] The present invention relates to compounds that are ATX modulators, especially ATX inhibitors, and methods of making and using such compounds. Background of the invention [0004] Autotaxin (ATX, ENPP2) is an autotaxin motility stimulator originally isolated from the supernatant of melanoma cells and widely present in biological fluids, including blood, cancer ascites, synovial fluid, pleural fluid and secreted glycoproteins in cerebrospinal fluid (Stracke, M.L., et al. Identification, purification, and partial sequence analysis of autotaxin, a novel mobility-stimulating protein. J Biol Chem 267,2524-2529 (1992), which is cited in its entirety incorporated into this article). ATX is encoded by a single gene on human chromosome 8 (mouse chromosome 15), and its tr...

Claims

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Application Information

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IPC IPC(8): A61K31/015A61K31/4375A61K31/44
CPCC07C2101/14C07C229/48A61K31/439C07D223/06C07D211/62C07C217/22C07C2101/08A61K31/445C07D295/096C07D217/22C07C2102/42A61K31/55A61K31/196C07D209/52C07D221/22A61K31/5375C07B2200/07C07C255/59A61K45/06C07D211/34C07D471/08C07C229/46A61K31/136A61K31/46C07C2101/04C07C2601/04C07C2601/08C07C2601/14C07C2602/42A61K31/472A61K31/4725C07D401/06C07D451/02A61P11/00A61P11/06A61P19/02A61P25/00A61P25/04A61P25/16A61P25/28A61P29/00A61P35/00A61P37/00A61P37/02A61P37/06A61P43/00A61P9/10A61P3/10Y02A50/30C07C229/50C07D211/60
Inventor K·古基安G·库马拉维尔马斌米莎彭海若邵朝晖孙立红A·塔维拉斯汪德平忻芷莉张蕾
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