Monocarboxylate transport modulators and uses thereof

一种选自、药学的技术，应用在单羧酸转运蛋白调节剂及其用途领域，能够解决没有应用癌症治疗等问题

Active Publication Date: 2017-11-28
NEGI THERAPEUTICS
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

This fundamental distinction between normal and cancer cells has been applied to cancer diagnosis, but not to cancer treatment

Method used

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  • Monocarboxylate transport modulators and uses thereof
  • Monocarboxylate transport modulators and uses thereof
  • Monocarboxylate transport modulators and uses thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0313]

[0314] step 1

[0315]

[0316] method

[0317] In a 250 mL 3-necked round bottom flask, 3-chloro-4-fluoroaniline (20 g, 137.4 mmol) and toluene (100 mL) were added. To the reaction mixture was added diethyl-2-(ethoxymethylene)malonate (29.7 g, 137.4 mmol) at 25°C. The reaction mixture was heated at reflux and stirred for 1 h, then cooled to 30 °C and water (150 mL) was added and the mixture was extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine solution, washed with anhydrous Na 2 SO 4 Drying and concentration under reduced pressure afforded 40 g of crude product which was titrated with a minimal amount of cyclohexane to give diethyl-2-(3-chloro-4-fluorophenylamino)methylenemalonate (1) 36g, yield (50.1%); 1 H NMR (400MHz, DMSO-d 6): δ10.61(d, J=12.8,1H),8.29(d,J=13.6,1H),7.72-7.74(m,1H),7.4-7.42(m,2H),4.12-4.2(m, 4H), 1.24-1.26 (m, 6H); MS (ESI): 316.1 (M+H).

[0318] step 2

[0319]

[0320] In a 500 mL 3-neck rou...

Embodiment 2

[0331] The remaining mother liquor from the synthesis of Example 1 was concentrated under reduced pressure to obtain crude 5b. The product was purified by column chromatography (silica gel) to obtain 10 mg of pure 6-(benzyl(methyl)amino)-7-chloro-1-isobutyl-4-oxo-1,4-dihydroquinoline- 3-Carboxylic acid (5b): yield, 5%; 1 H NMR (400MHz, DMSO-d 6 ):δ15.16(d,1H),8.95(s,1H),7.28-8.27(m,7H),4.41-4.43(d,2H),4.3(s,2H),2.74(s,3H), 2.1-2.2 (m, 1H), 0.88-0.90 (d, 6H); MS (ESI): 399 (M+H); HPLC: 93.57%.

Embodiment 3

[0333]

[0334] In a 25 mL single necked round bottom flask were added intermediate 4 (0.5 g, 1.679 mmol) from Example 1 and N-1-(3-(trifluoromethyl)phenyl)methanamine (1.5 g, 8.39 mmol) ) and heated to 120°C for 24h. The reaction was monitored for completion by TLC, worked up aqueous and acidified to pH 3-4 with 1 N HCl. The aqueous layer was extracted with EtOAc and the organic layer was washed with anhydrous Na 2 SO 4 dry. The solvent was evaporated under reduced pressure to obtain a crude product which was purified by silica gel column chromatography to obtain pure 6-fluoro-1-isobutyl-7-(methyl(3-(trifluoromethyl)benzyl) Amino)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (5), (25mg); Yield: 3.3%; 1 H NMR (400MHz, DMSO-d 6 ):δ15.5(s,1H),6.83-8.71(m,7H),4.75(s,2H),4.20(d,2H),3.13(s,3H),1.83-1.86(m,1H), 0.74-0.76 (d,6H); MS (ESI): 451.1 (M+H); HPLC: 92.07%.

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PUM

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Abstract

The invention generally relates to the field of monocarboxylate transport modulators, e.g., monocarboxylate transport inhibitors, and more particularly to new substituted-quinolone compounds, the synthesis and use of these compounds and their pharmaceutical compositions, e.g., in treating, modulating, forestalling and / or reducing physiological conditions associated with monocarboxylate transport activity such as in treating cancer and other neoplastic disorders, inflammatory diseases, disorders of abnormal tissue growth and fibrosis including cardiomyopathy, obesity, diabetes, cardiovascular diseases, tissue and organ transplant rejection, and malaria.

Description

[0001] Cross References to Related Applications [0002] This application claims priority to US Provisional Application 62 / 080,703, filed November 17, 2014, the entire contents of which are hereby incorporated by reference. technical field [0003] The present application relates to compounds useful as modulators of monocarboxylate transporters. The application also provides pharmaceutically acceptable compositions comprising the compounds of the application and methods of using said compositions in the treatment of various conditions. Background technique [0004] It has been well documented that tumors exhibit altered cellular metabolism, with cancer cells displaying a high proportion of glucose consumption. Tumors contain better oxidized (aerobic) regions, and poorer oxidized (hypoxic) regions. In contrast to normal cells, cancer cells rely heavily on aerobic glycolysis (Warburg effect, 1956) or anaerobic glycolysis (in hypoxic regions) for energy production (ATP). Th...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D215/56A61K31/435C07D401/06
CPCA61P3/00A61P3/04A61P3/10A61P29/00A61P33/06A61P35/00A61P37/06A61P43/00C07D215/56C07D401/06C07D401/12C07D401/14C07D405/12C07D409/12C07D413/12C07D417/12C07D471/04Y02A50/30
Inventor 文森特·S吴琼
Owner NEGI THERAPEUTICS
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