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Combinations of a 4-pyrimidinesulfamide derivative with active ingredients for the treatment of endothelin related diseases

A technology of active ingredients and compositions, applied in the field of combination of 4-pyrimidinesulfonamide derivatives and active ingredients for the treatment of endothelin-related diseases, capable of solving problems such as increased side effects

Pending Publication Date: 2019-10-11
IDORSIA PHARM LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

WO2016 / 073846 provides further examples where fluid retention may lead to increased side effects of ERA bosentan, tizosentan, ambrisentan and atrasentan

Method used

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  • Combinations of a 4-pyrimidinesulfamide derivative with active ingredients for the treatment of endothelin related diseases
  • Combinations of a 4-pyrimidinesulfamide derivative with active ingredients for the treatment of endothelin related diseases
  • Combinations of a 4-pyrimidinesulfamide derivative with active ingredients for the treatment of endothelin related diseases

Examples

Experimental program
Comparison scheme
Effect test

preparation example Construction

[0085] The preparation of pharmaceutical compositions can be carried out in a manner familiar to the person skilled in the art (see for example Remington, The Science and Practice of Pharmacy, 21st Edition (2005), Part 5, "Pharmaceutical Manufacturing" [published by Lippincott Williams & Wilkins]): by The crystalline forms of the present invention, optionally in combination with other therapeutically useful substances, are formulated together with suitable, nontoxic, inert, pharmaceutically acceptable solid or liquid carrier materials and (if desired) customary pharmaceutical adjuvants. In galenical form.

[0086] 23) Another embodiment relates to any one of embodiments 1) to 22), in particular to a solid medicament according to any one of embodiments 8) to 14), or according to any one of embodiments 15) to 21) Composition, especially in the form of a tablet, comprising inert microcrystalline cellulose, lactose, hydroxypropyl cellulose, croscarmellose sodium and stearic acid a...

Embodiment 1

[0172] Example 1: Form A:

[0173] 1.1. Add 5-(4-bromophenyl)-4-(2-((5-bromopyrimidin-2-yl)oxy)ethoxy)-6-fluoropyrimidine ( 100g, 0.213mol, 1 equivalent), sulfonamide (40.9g, 0.425mol, 2.0 equivalent), K 2 CO 3 (147 g, 1.06 mol, 5 eq) and DMSO (500 mL, 5 vol) spiked with water (2 mL, 0.111 mol, 0.5 eq). The heterogeneous mixture was heated to about 70° C. in about 3 hours, after which time complete conversion was observed. After cooling to 20°C, most of the inorganic salt material was removed by filtration. The filter cake was washed with EtOAc / iPrOAc 1:1 (300 mL, 3 vol). Celite (100 g, 1 wt.) topped with a layer of charcoal (20 g, 0.2 wt.) was pretreated with EtOAc / iPrOAc 1:1 (500 mL, 5 vol.) (filtrate discarded). The reaction mixture was filtered through the filter cake and washed with EtOAc / iPrOAc 1:1 (300 mL, 3 vol). Then 1 M aqueous NaOAc (500 mL, 0.5 mol, 2.3 eq, 5 vol) was added while maintaining the temperature at 25-35 °C. The aqueous phase was washed a second ...

Embodiment 2

[0175] Example 2: Form B (the DCM solvate of the COMPOUND):

[0176] 5-(4-Bromophenyl)-4-(2-((5-bromopyrimidin-2-yl)oxy)ethoxy)-6-fluoropyrimidine (10.0g, 21.3mmol, 1.00eq), sulfo Amide (4.1 g, 42.5 mmol, 2.0 equiv) and K 2 CO 3 (14.7 g, 106 mmol, 5.0 equiv) was suspended in DMSO (50 mL, 5 vol) and heated to 70 °C for 5 hours. The mixture was cooled to room temperature and EtOAc (40 mL, 4 vols) was added followed by water (100 mL, 10 vols). After separation of the layers (organic phase discarded), the aqueous phase was extracted with DCM (100 mL, 10 vol). The DCM layer was acidified from pH 11.5 to pH 7.0 with concentrated AcOH (3 mL, 52 mmol, 2.5 equiv), resulting in crystallization of the product. The suspension was cooled to 0°C for 1 hour, then to -5°C for 15 minutes. The solid was filtered, washed with cold DCM (10 mL, 1 vol) and dried to give {5-(4-bromo-phenyl)-6-[2-(5-bromo-pyrimidin-2-yl-oxy)-ethyl Oxy]-pyrimidin-4-yl}-sulfonamide in DCM solvate as a white solid...

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Abstract

The present invention concerns the compound aprocitentan, {5-(4-bromo-phenyl)-6-[2-(5-bromo-pyrimidin-2-yloxy)-ethoxy]-pyrimidin-4-yl}-sulfamide, and its use as endothelin receptor antagonist, in combination with other active ingredients or therapeutic agents including an angiotenin receptor blocker, and / or a calcium channel blocker, and preferably a diuretic which is a thiazide-like diuretic, inthe prophylaxis or treatment of certain endothelin related diseases. The invention further relates to pharmaceutical compositions comprising aprocitentan in combination with said other active ingredients or therapeutic agents. The invention further relates to such pharmaceutical compositions comprising novel crystalline forms of aprocitentan.

Description

technical field [0001] The present invention relates to the compound aprocitentan and its use as an endothelin receptor antagonist in combination with other active ingredients or therapeutic agents including angiotensin receptor blockers (especially valsartan), and / or calcium channel blockers (especially Amlodipine), and preferably a diuretic (which is a thiazide diuretic (especially hydrochlorothiazide or chlorthalidone)) in combination for the prevention or treatment of some endothelin-related diseases. The present invention further relates to pharmaceutical compositions comprising aprocitentan in combination with said other active ingredients or therapeutic agents. The present invention also relates to pharmaceutical compositions comprising novel crystalline forms of aprocitentan; pharmaceutical compositions prepared from such crystalline forms, and to combinations of said crystalline forms with said other active ingredients or therapeutic agents for prophylaxis or treatmen...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/41A61K31/4422A61K31/513A61K31/549A61P9/12
CPCC07D239/47A61P9/12A61P9/10A61P29/00A61P1/00A61P1/04A61P35/00A61P13/08A61P15/10A61P27/16A61P11/00A61P11/06A61P13/12A61P3/06A61P27/06C07B2200/13A61K31/506A61K45/06A61K31/401A61K31/41A61K2300/00A61K31/4035A61K31/549A61K31/513A61K31/4422A61P9/00A61P9/04C07D403/12A61K31/4418
Inventor 马克·贝列特马汀·波利马丁尼·克劳泽马克·艾格拉尔兹菲利普·科勒伊凡·申德尔霍尔兹马库斯·冯劳默尔
Owner IDORSIA PHARM LTD
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