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Thiazolyl piperdine derivatives

A technology of groups and compounds, applied in the field of thiazolylpiperidine derivatives, can solve problems such as failure to identify interaction partners

Inactive Publication Date: 2011-05-18
MERCK PATENT GMBH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, no intracellular interaction partners of S1P have been identified

Method used

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  • Thiazolyl piperdine derivatives
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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0361] 4-(2-Methyl-3-{4-[4-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)thiazol-2-yl ]Piperidin-1-yl}propyl)morpholine ("A1") Preparation

[0362]

[0363] 200 mg (0.46 mmol) of 4-[4-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)thiazol-2-yl]piperidine hydrogen Bromate with 122 mg (0.69 mmol) of 4-(3-chloro-2-methyl-propyl)morpholine in 5 mL of ethanol and 320 μL (2.3 mmol) of triethylamine, in microwave, irradiated at 160 °C 2 hours. The reaction mixture was evaporated and purified by silica gel column chromatography. The product was further purified by preparative HPLC.

[0364] Yield: 49 mg of "A1" trifluoroacetate salt, pale yellow oil; ESI: 496 g / mol [M+H], HPLC: Rt.=1.94 min.

Embodiment 2

[0366] 1'-Ethyl-4-[4-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)thiazol-2-yl]-[1, Preparation of 3'] Bipiperidine ("A2")

[0367]

[0368] 500 mg (1.41 mmol) of 4-[4-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)thiazol-2-yl]piperidine were mixed with 210 mg (1.42 mmol) of 3-chloro-1-ethylpiperidine, 360 mg (4.29 mmol) of sodium bicarbonate, and 210 mg (1.40 mmol) of sodium iodide were suspended in 40 mL of DMF and placed in a microwave at 120 Irradiated for 6 hours at °C. The reaction mixture was evaporated and the residue was dissolved in ethyl acetate and 0.1N NaOH. The organic phase was separated, evaporated and purified by silica gel column chromatography.

[0369] Yield: 45 mg of "A2" hydrochloride, brown crystals, ESI: 466 g / mol [M+H];

[0370] 1 H NMR (500MHz, DMSO-d 6 ) δ [ppm] 11.19(b, 1H), 7.93(s, 1H), 7.65(s, 2H), 7.11(d, J=8.4, 1H), 3.0-4.0 (overlap, 7H), 2.76(d, J=19.6, 4H), 2.15-2.45 (b, 5H), 1.85-2.10 (m, 4H), 1.73-1.82 (m, 4H), 1...

Embodiment 3

[0381] (2-{4-[4-(5,5,8,8-Tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)thiazol-2-yl]piperidin-1-yl Preparation of} ethyl) tert-butyl carbamate ("A37")

[0382]

[0383] 10 mL of THF and 200 μL of glacial acetic acid were added to 200 mg (0.46 mmol) of 4-[4-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl] ) thiazol-2-yl]piperidine hydrobromide, and 154 mg (0.92 mmol) of tert-butyl (2-oxoethyl)carbamate was added. 195 mg (0.92 mmol) of sodium triacetoxyborohydride were then added and the reaction mixture was stirred at room temperature for 24 hours. The reaction mixture was filtered, the mother liquor was evaporated and the residue was purified by preparative HPLC to give "A37";

[0384] ESI: 498 (M+H), HPLC: 3.34 min.

[0385] The following compounds were prepared analogously to the methods described above:

[0386]

[0387]

[0388]

[0389]

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Abstract

The invention relates to compounds of formula (I), wherein R1, R2, R3, R4, R5, R6, R9, R10, R11, Q and W are as defined in claim 1 and precursors thereof are inhibitors of spingosine kinase and can be used, for instance, for the treatment of tumors.

Description

Background of the Invention [0001] The object of the present invention is to discover new compounds with valuable properties, especially those which can be used for the preparation of medicaments. [0002] The present invention relates to compounds and the use of these compounds in the treatment of diseases associated with elevated levels of sphingosine phosphate, and to pharmaceutical compositions comprising these compounds. [0003] In particular, the present invention relates to compounds of formula I, which preferably inhibit the enzyme sphingosine kinase 1, which regulates sphingosine phosphate levels by phosphorylation of sphingosine, compositions comprising these compounds and the use of these Compounds to treat diseases and complaints such as cancer, tumor formation, growth and spread, arteriosclerosis, ocular diseases, choroidal neovascularization and diabetic retinopathy, inflammatory diseases, arthritis, neurodegeneration, restenosis, cardiac disease, wound healing...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D417/04C07D417/14A61K31/427A61P35/00
CPCC07D417/14A61K31/427C07D417/12C07D277/28C07D417/04A61K45/06A61P1/00A61P1/04A61P1/16A61P11/00A61P11/06A61P13/12A61P17/00A61P17/02A61P17/06A61P17/10A61P19/02A61P25/00A61P27/02A61P27/06A61P29/00A61P35/00A61P35/02A61P37/02A61P37/06A61P37/08A61P9/00A61P9/10A61P3/10A61K2300/00
Inventor F·施蒂贝尔T·海因里希D·维恩克
Owner MERCK PATENT GMBH
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