Heteroaromatic sulfonamide prodrugs

A technology of sulfonamide and heteroaromatic group is applied in the application field of preparing these prodrugs and preparing oral medicines, and can solve the problems of not providing active compounds, reducing metabolism and the like

Inactive Publication Date: 2008-12-10
BAYER SCHERING PHARMA OY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Disadvantageously, although use of this formulation was shown to reduce metabolic effects, it did not provide therapeutically relevant levels of the active compound

Method used

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  • Heteroaromatic sulfonamide prodrugs
  • Heteroaromatic sulfonamide prodrugs
  • Heteroaromatic sulfonamide prodrugs

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0079] Example 1: 3-tert-butyldimethylsilyloxyestra-1,3,5(10)-trien-17β-yl 6'-sulfamo acyl nicotinate

[0080] Under argon, 0.5 g of 3-tert-butyldimethylsilyloxyestra-1,3,5(10)-trien-17β-ol and 0.5 g of 6-sulfamoylnicotinic acid were dissolved in 7ml of pyridine. Then 0.1 g of p-Tos-OH was added and finally 0.5 g of DCC was added at 0°C. After 48 hours, the reaction mixture was stirred at room temperature. For work-up, 40 ml of water were added and the mixture was adjusted to pH~6 with 10% strength HCl. The precipitated material was filtered off, washed with water and dried. Purification by chromatography on silica gel affords 3-tert-butyldimethyl-silyloxyestra-1,3,5(10)-trien-17β-yl 6'-sulfamoyl-nicotinate .

[0081] 1 H-NMR (DMSO-d 6 ): 0.16(s, 6H, SiMe), 0.938(s, 9H, t-Bu), 0.944(s, 3H, 18-Me), 4.90(t, 1H, 17-H), 6.50-7.15(3m, 3H, CH Ar ), 7.69 (s, 2H, NH 2 ), 8.06, 8.55, 9.16 (3m, 3H, CH Py ).

Embodiment 2

[0082] Example 2: 3-Hydroxyestro-1,3,5(10)-trien-17β-yl 6'-sulfamoyl-nicotinate (1)

[0083] 300 mg of 3-tert-butyldimethylsilyloxyestra-1,3,5(10)-trien-17β-yl 6'-sulfamoylnicotinate was dissolved in 20 ml of THF. 250 mg of TBAF were added with stirring at room temperature. After 1 hour, 20 ml of water were added with stirring. This material was extracted with ethyl acetate. The organic phase was washed with saturated NaCl solution in MgSO 4 Drying, filtration, concentration and chromatographic purification on silica gel affords 3-hydroxyestra-1,3,5(10)-trien-17β-yl 6'-sulfamoyl nicotinate.

[0084] 1 H-NMR (DMSO-d 6 ): 0.94 (s, 3H, 18-Me), 4.90 (t, 1H, 17-H), 6.40-7.15 (3m, 3H, CH Ar ), 7.69 (s, 2H, NH 2 ); 8.06, 8.55 (2m, 2H, CH Py ), 9.02 (s, 1H, 3-OH), 9.17 (1s, 1H, CH Py ).

Embodiment 3

[0085] Example 3: 3-tert-butyldimethylsilyloxyestra-1,3,5(10)-trien-17β-yl 5'-sulfamo acyl nicotinate

[0086] Under argon, 0.55 g of 3-tert-butyldimethylsilyloxyest-1,3,5(10)-trien-17β-ol and 0.55 g of 5-sulfamoylnicotinic acid were dissolved in 7ml of pyridine. Then 0.12 g of p-Tos-OH were added and finally 0.55 g of DCC were added at 0°C. After 48 hours, the reaction mixture was stirred at room temperature. For work-up, 40 ml of water were added and the mixture was adjusted to pH~6 with 10% strength HCl. The precipitated material was filtered off, washed with water and dried. Chromatographic purification on silica gel yields 3-tert-butyldimethyl-silyloxyestra-1,3,5(10)-trien-17β-yl 5'-sulfamoyl-nicotinate .

[0087] 1 H-NMR (DMSO-d 6 ): 0.16(s, 6H, SiMe), 0.94(s, 9H, t-Bu), 0.95(s, 3H, 18-Me), 4.92(t, 1H, 17-H), 6.5-7.2(3m, 3H, CH Ar ), 7.79 (s, 2H, NH 2 ), 8.6-9.3 (3m, 3H, CH Py ).

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Abstract

The invention relates to the sulfonamide prodrugs of formula (I), comprising a heteroaromatic linker, to a method for producing the same, to pharmaceutical compositions containing said compounds and to their use for producing orally available drugs. The compounds according to the invention bind to carboanhydrases and inhibit these enzymes.

Description

technical field [0001] The present invention relates to sulfonamide prodrugs of general formula (I): [0002] [0003] wherein X is heteroaromatic. The invention also relates to processes for the preparation of these prodrugs, pharmaceutical compositions comprising these compounds, and their use in the preparation of oral medicaments. Background technique [0004] WO 01 / 91797 discloses through the group -SO 2 NR 1 R 2 Steroids that bind to and accumulate in red blood cells. The concentration ratio of these compounds between erythrocytes and plasma is 10-1000:1, preferably 30-1000:1, thus we can be called long-acting preparations in erythrocytes. Because of the strong binding of these compounds to erythrocytes, metabolic effects during hepatic passage are avoided. Disadvantageously, although the use of this formulation was shown to reduce metabolic effects, it did not provide therapeutically relevant levels of the active compound. The reasons for this are believed t...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/565A61K31/5685A61P15/02A61P15/08A61P35/00A61P43/00
CPCA61K31/565A61K31/5685A61K31/59C07J33/00C07J43/00A61P15/00A61P15/02A61P15/08A61P15/18A61P29/00A61P35/00A61P37/08A61P43/00A61P5/00A61K31/64
Inventor R·维尔瓦R·努比迈尔
Owner BAYER SCHERING PHARMA OY
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