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Combination products of irak4 inhibitors and btk inhibitors

A technology of combined products and pharmaceuticals, which is applied in the direction of drug combinations, medical preparations containing active ingredients, active ingredients of heterocyclic compounds, etc., and can solve problems such as non-combined products

Active Publication Date: 2021-07-09
BAYER PHARMA AG
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0094] 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 a pharmaceutically acceptable salt thereof

Method used

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  • Combination products of irak4 inhibitors and btk inhibitors
  • Combination products of irak4 inhibitors and btk inhibitors
  • Combination products of irak4 inhibitors and btk inhibitors

Examples

Experimental program
Comparison scheme
Effect test

preparation example Construction

[0440] Similar to the preparation of Intermediate 4-4 (Preparation Method 2), 195 mg of 5-amino-2-(3-hydroxy-3-methylbutyl)-2H-indazole-6-carboxylic acid methyl ester ( Intermediate 7-1) was reacted with 70 mg of 6-picoline-2-carboxylic acid. 278 mg of the title compound were obtained as crude product after similar aqueous work-up.

[0441] UPLC-MS (Method A1): R t = 1.14 min (UV detector: TIC), found mass 396.00.

[0442] Intermediates 4-10

[0443] 2-[3-(2,2,2-Trifluoroethoxy)propyl]-5-({[6-(trifluoromethyl)pyridin-2-yl]carbonyl}amino)-2H-indazole -6-methyl carboxylate

[0444]

[0445] 250mg 5-({[6-(trifluoromethyl)pyridin-2-yl]carbonyl}amino)-1H-indazole-6-carboxylic acid methyl ester (intermediate 7-1), 193mg 3-bromopropyl 2, A mixture of 2,2-trifluoroethyl ether, 242 mg potassium carbonate and 145 mg potassium iodide in 3 ml DMF was stirred at 100° C. for 20 hours. Water was added, the mixture was extracted with ethyl acetate and the extract was washed with so...

Embodiment 1

[0470] N-[6-(2-Hydroxypropan-2-yl)-2-(2-methoxyethyl)-2H-indazol-5-yl]-6-(trifluoromethyl)pyridine-2- Formamide

[0471]

[0472] 75mg (0.18mmol) 2-(2-methoxyethyl)-5-({[6-(trifluoromethyl)pyridin-2-yl]carbonyl}amino)-2H-indazole-6-carboxylic acid The methyl ester (interm. 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.

[0473] UPLC-MS (Method A1): R t =1.08min

[0474] MS (ESIpos): m / z=423 (M+H) +

[0475] 1 H NMR (300MH...

Embodiment 2

[0477] N-[6-(Hydroxymethyl)-2-(2-methoxyethyl)-2H-indazol-5-yl]-6-(trifluoromethyl)pyridine-2-carboxamide

[0478]

[0479] 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.

[0480] UPLC-MS (Method A2): R t =0.97min

[0481] MS(ESIpos): m / z=409(M+H) +

[0482] 1 H NMR (400MHz, DMSO-d6): 6[ppm]=1.62(s, 6H), 3.86(q, 2H), 4.43(t, 2H), 4.95(t, 1H), 5.94(s, 1H), 7.57(s, 1H), 8.16(dd, 1H), 8.30(s, 1H), 8.37(t, 1H), 8.45(d, 1H), 8.72(s, 1H), 12.36...

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Abstract

The present application relates to a novel combination product of at least two components (component A and component B) for the treatment and / or prevention of diseases: 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; component B is a BTK inhibitory compound, or a pharmaceutically acceptable salt thereof; and, optionally One or more components C which are pharmaceutical products; 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, And to its use for the manufacture of a medicament for the treatment and / or prevention of diseases, in particular for the treatment and / or prevention of endometriosis, lymphoma, macular degeneration, COPD, neoplastic disorders and psoriasis.

Description

technical field [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 inhibi...

Claims

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Application Information

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Patent Type & Authority Patents(China)
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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