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Glucose transport inhibitors

A technology of alkyl and group, which is applied in the field of intermediate compounds for the preparation of the compound, and can solve problems such as no specific disclosure

Inactive Publication Date: 2017-08-18
BAYER PHARMA AG
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0012] However, the above prior art does not specifically disclose the compounds of general formula (I) of the present invention or their tautomers, stereoisomers, N- Oxides, hydrates, solvates or salts, or mixtures thereof, or their pharmacological activity

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0988] N-[1-(4-fluorobenzyl)-3-methyl-1H-pyrazol-4-yl]-2,6-dimethylquinoline-4-carboxamide

[0989]

[0990] To 245 mg (1.19 mmol) 1-(4-fluorobenzyl)-3-methyl-1H-pyrazol-4-amine and 1-(4-fluorobenzyl)-5-methyl-1H-pyrazole -453 mg (1.19 mmol) HATU, 0.26 mL N , N - Diisopropylethylamine and 200 mg (0.99 mmol) of commercially available 2,6-dimethylquinoline-4-carboxylic acid. The reaction mixture was stirred at 25°C for 20 hours. The mixture was directly purified by preparative HPLC (Method A1) to obtain 208 mg (51%) of the desired title compound and 92 mg (23%) of the regioisomer N-[1-(4-fluorobenzyl)-5 -Methyl-1H-pyrazol-4-yl]-2,6-dimethylquinoline-4-carboxamide.

[0991] 1H NMR (500 MHz, DMSO d 6 ): δ (ppm) = 2.18 (s, 3H), 2.48 (s, 3H), 2.68(s, 3H), 5.25 (s, 2H), 7.19 (t, 2H), 7.36 (dd, 2H), 7.50 (s, 1H), 7.60 (dd, 1H), 7.80 (s, 1H), 7.89 (d, 1H), 8.23 ​​(s, 1H), 10.21 (s, 1H).

Embodiment 2

[0993] 6,7-Difluoro-N-[1-(4-fluorobenzyl)-3-methyl-1H-pyrazol-4-yl]-2-(trifluoromethyl)quinoline-4-carboxamide

[0994]

[0995] Similar to Example 1), 222 mg (1.08 mmol) of 1-(4-fluorobenzyl)-3-methyl-1H-pyrazol-4-amine and 1-(4-fluorobenzyl)-5- A mixture of methyl-1H-pyrazol-4-amine (Intermediate 1C) and 250 mg (0.90 mmol) 6,7-difluoro-2-(trifluoromethyl)quinoline-4-carboxylic acid (Intermediate 5A ) reaction to give 137 mg (32%) of the desired title compound and 72 mg (17%) of the regioisomer 6,7-difluoro-N-[1-(4- fluorobenzyl)-5-methyl-1H-pyrazol-4-yl]-2-(trifluoromethyl)quinoline-4-carboxamide.

[0996] 1H NMR (400 MHz, DMSO d 6 ): δ (ppm) = 2.18 (s, 3H), 5.25 (s, 2H), 7.15- 7.22 (m, 2H), 7.35 (dd, 2H), 8.17 - 8.27 (m, 3H), 8.38 (dd, 1H), 10.44 (s,1H).

Embodiment 3

[0998] N-[1-(4-fluorobenzyl)-3-methyl-1H-pyrazol-4-yl]-2-methoxyquinoline-4-carboxamide

[0999]

[1000] Similar to Example 1), 303 mg (1.48 mmol) of 1-(4-fluorobenzyl)-3-methyl-1H-pyrazol-4-amine and 1-(4-fluorobenzyl)-5- A mixture of methyl-1H-pyrazol-4-amine (Intermediate 1C) was reacted with 250 mg (1.23 mmol) of commercially available 2-methoxyquinoline-4-carboxylic acid after purification by HPLC (Method C1) This gave 201 mg (37%) of the desired title compound and 97 mg (19%) of the regioisomer N-[1-(4-fluorobenzyl)-5-methyl-1H-pyrazol-4-yl ]-2-methoxyquinoline-4-carboxamide.

[1001] 1H NMR (500 MHz, DMSO d 6): δ (ppm) = 2.16 (s, 3H), 4.03 (s, 3H), 5.24(s, 2H), 7.16 - 7.21 (m, 3H), 7.31 - 7.37 (m, 2H), 7.47 (ddd, 1H), 7.71 (ddd, 1H), 7.84 (d, 1H), 7.97 (dd, 1H), 8.22 (s, 1H), 10.23 (s, 1H).

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Abstract

The present invention relates to chemical compounds that selectively inhibit glucose transporter 1 (GLUT1), to methods of preparing said compounds, to pharmaceutical compositions and combinations comprising said compounds, to the use of said compounds for manufacturing a pharmaceutical composition for the treatment or prophylaxis of a disease, as well as to intermediate compounds useful in the preparation of said compounds.

Description

[0001] The present invention relates to compounds that selectively inhibit glucose transporter 1 (GLUT1), methods for preparing the compounds, pharmaceutical compositions and combinations containing the compounds, and uses of the compounds for preparing pharmaceutical compositions for treating or preventing diseases , and intermediate compounds useful in the preparation of said compounds. [0002] Background of the invention [0003] Glucose is an essential substrate for metabolism in most cells. Because glucose is a polar molecule, transport across biomembranes requires specific transporters. Glucose transport across the apical membrane of intestinal and renal epithelial cells depends on secondary active Na + / the presence of glucose symporters SGLT-1 and SGLT-2, which concentrate glucose inside the cell, using Na + The energy provided by the co-transport of ions along their electrochemical gradient. Additionally, the facilitated diffusion of glucose across cell membranes ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D401/14C07D413/14C07D215/50C07D231/38C07D401/06C07D401/12C07D403/06C07D413/06C07D417/06C07D417/14A61K31/4709A61P35/00A61P17/06A61P35/04A61P35/02A61P13/08
CPCC07D215/50C07D231/38C07D401/06C07D401/12C07D401/14C07D403/06C07D413/06C07D413/14C07D417/06C07D417/14A61K31/4709A61K31/136A61K31/337A61K31/513A61K31/555A61K31/573A61K31/675A61K31/704A61P13/08A61P17/06A61P35/00A61P35/02A61P35/04A61P43/00A61K2300/00
Inventor B.布赫曼I.海斯勒T.米勒A.克莱韦M.赫劳尔特R.诺伊豪斯H.彼得鲁尔M.宽茨-舍费尔
Owner BAYER PHARMA AG
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