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Combinations of inhibitors of irak4 with inhibitors of btk

A technology of combination products and compounds, applied in the field of treatment or prevention of neoplastic diseases, kits, and medicaments for the treatment of neoplastic diseases, can solve the problem of not containing combination products and the like

Active Publication Date: 2018-04-03
BAYER PHARMA AG
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0093] However, the prior art does not contain any combination product as described in the present invention, said combination product containing the IRAK4 inhibitory compound of formula (I) or its diastereoisomers, enantiomers as defined herein , metabolites, salts, solvates or solvates of salts, and ibrutinib, or pharmaceutically acceptable salts thereof

Method used

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  • Combinations of inhibitors of irak4 with inhibitors of btk
  • Combinations of inhibitors of irak4 with inhibitors of btk
  • Combinations of inhibitors of irak4 with inhibitors of btk

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0454] N-[6-(2-Hydroxypropan-2-yl)-2-(2-methoxyethyl)-2H-indazol-5-yl]-6-(trifluoromethyl)pyridine-2- Formamide

[0455]

[0456] 75mg (0.18mmol) 2-(2-methoxyethyl)-5-({[6-(trifluoromethyl)pyridin-2-yl]carbonyl}amino)-2H-indazole-6-carboxylic acid The methyl ester (intermediate 4-2) was dissolved in 500 μl THF and mixed together with 887 μl (0.89 mmol) of 1M methylmagnesium bromide in THF. The reaction mixture was stirred at 25°C for 60 minutes. Subsequently, 1 ml of saturated aqueous ammonium chloride solution was carefully added and the mixture was filtered. The aqueous phase was extracted twice with ethyl acetate, and the organic phases were combined, filtered through a hydrophobic filter and concentrated. The residue was dissolved in 3 ml DMSO and purified by preparative HPLC. Fractions containing product were lyophilized. This gave 20 mg of the title compound.

[0457]

Embodiment 2

[0459] N-[6-(Hydroxymethyl)-2-(2-methoxyethyl)-2H-indazol-5-yl]-6-(trifluoromethyl)pyridine-2-carboxamide

[0460]

[0461] 13 mg (0.36 mmol) lithium aluminum hydride were suspended in 1 ml THF and the mixture was cooled to 0°C. 75 mg (0.17 mmol) 2-(2-methoxyethyl)-5-({[6-(trifluoromethyl)pyridin-2-yl]carbonyl}amino)- 2H-Indazole-6-carboxylic acid methyl ester (Intermediate 4-2) and the mixture was stirred at 25°C for 60 minutes. The mixture was diluted with water and extracted twice with ethyl acetate, and the combined organic phases were washed with sodium chloride solution, filtered through a hydrophobic filter, concentrated and dried under reduced pressure. This gave 36 mg of the title compound.

[0462]

Embodiment 3

[0464] N-[6-(2-Hydroxypropan-2-yl}2-(3-methoxypropyl)-2H-indazol-5-yl]-6-(trifluoromethyl)pyridine-2-methyl Amide

[0465]

[0466]Make 75mg (0.17mmol) 2-(3-methoxypropyl)-5-({[6-(trifluoromethyl)pyridin-2-yl]carbonyl}amino)-2H-indazole-6-carboxylic acid The methyl ester (intermediate 4-3) was dissolved in 500 μl THF and mixed with 859 μl (0.86 mmol) of a 1M solution of methylmagnesium bromide in THF. The reaction mixture was stirred at 25°C for 60 minutes. Subsequently, 1 ml of saturated ammonium chloride solution was carefully added and the mixture was filtered. The aqueous phase was extracted twice with ethyl acetate, and the organic phases were combined, filtered through a hydrophobic filter and concentrated. The residue was dissolved in 3 ml DMSO and purified by preparative HPLC. Fractions containing product were freeze-dried. This gave 25 mg of the title compound.

[0467]

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Abstract

The present application relates to novel combinations of at least two components, component A and component B: component A is an IRAK4-inhibiting compound of the formula (I) as defined herein, or a diastereomer, an enantiomer, a metabolite, a salt, a solvate or a solvate of a salt thereof; component B is a BTK-inhibiting compound, or a pharmaceutically acceptable salt thereof; and, optionally, oneor more components C which are pharmaceutical products; in which one or two of the above-defined compounds A and B are optionally present in pharmaceutical formulations ready for simultaneous, separate or sequential administration, for treatment and / or prophylaxis of diseases, and to the use thereof for production of medicaments for treatment and / or prophylaxis of diseases, especially for treatment and / or prophylaxis of endometriosis, lymphoma, macular degeneration, COPD, neoplastic disorders and psoriasis.

Description

[0001] The present invention relates to a combination product of at least two components (component A and component B): [0002] Component A is an IRAK4 inhibitory compound of formula (I) as defined herein, or a diastereomer, enantiomer, metabolite, salt, solvate or solvate of a salt thereof; [0003] ●Component B is a BTK inhibitory compound; [0004] and, optionally, [0005] - one or more components C, which are medicinal products; [0006] wherein one or both of compounds A and B as defined above are optionally present in a pharmaceutical preparation intended for simultaneous, separate or sequential administration. [0007] Another aspect of the invention relates to a combination product of at least two components (component A and component B): [0008] Component A is an IRAK4 inhibitory compound of formula (I) as defined herein, or a diastereomer, enantiomer, metabolite, salt, solvate or solvate of a salt thereof; [0009] ●Component B is a BTK inhibitory compound selec...

Claims

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Application Information

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IPC IPC(8): A61K31/4439A61K31/454A61K31/496A61K31/497A61K31/4985A61K31/505A61K31/506A61K31/519A61K31/5377A61K31/55A61P35/00A61P35/02
CPCA61K31/4439A61K31/454A61K31/496A61K31/497A61K31/4985A61K31/505A61K31/506A61K31/519A61K31/5377A61K31/55A61K2300/00A61P35/00A61K45/06
Inventor U.博特A.M.温格纳H.西贝奈歇尔N.施密特R.努贝迈尔U.伯默J.京特H.施托伊贝尔M.朗格C.施特格曼A.苏特R.诺伊豪斯
Owner BAYER PHARMA AG
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