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4-(benzoimidazol-2-yl)-thiazole compounds and related aza derivatives

A compound, phenyl technology, applied in the field of CXCR3 receptor modulators, can solve the problem of low expression

Active Publication Date: 2014-10-08
IDORSIA PHARM LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The above three CXCR3 ligands are mainly expressed under inflammatory conditions, with very low expression in healthy tissues

Method used

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  • 4-(benzoimidazol-2-yl)-thiazole compounds and related aza derivatives
  • 4-(benzoimidazol-2-yl)-thiazole compounds and related aza derivatives
  • 4-(benzoimidazol-2-yl)-thiazole compounds and related aza derivatives

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0848] Example 1: 2-benzimidazol-1-yl-1-{4-[4-(1H-benzimidazol-2-yl)-thiazol-5-yl]-piperazin-1-yl}-B ketone:

[0849] 1.1 tert-butyl 4-(4-methoxycarbonyl-thiazol-5-yl)-piperazine-1-carboxylate:

[0850] To a solution of methyl 5-bromo-1,3-thiazole-4-carboxylate (10 g) in MeCN (120 mL) was added 1-Boc-piperazine (8.56 g) followed by DBU (10.1 mL). The resulting solution was stirred at 80 °C for 5 h. The reaction mixture was diluted with EA and water. The layers were separated and the organic phase was further washed with water. The combined aqueous layers were extracted with EA. by Na 2 SO 4 The combined organic layers were dried, filtered and evaporated in vacuo. The crude product was purified by CC (Biotage, SNAP 100 g cartridge, solvent A: Hept; solvent B: EA; gradient of %B: 2CV10%, 10 to 50% in 12CV, 3CV50%) to give 7.65g yellow oil. LC-MS(B):t R =0.79min; [M+H] + :328.37.

[0851]1.2.4-(4-Carboxyl-thiazol-5-yl)-piperazine-1-carboxylic acid tert-butyl ester:

...

Embodiment 8

[0861] Example 8: 1-{4-[4-(1H-benzimidazol-2-yl)-thiazol-5-yl]-piperazin-1-yl}-2-(6-chloro-imidazo[1 , 2-b] pyridazin-2-yl)-ethanone:

[0862] To 6-chloroimidazo[1,2-b]pyridazin-2-yl)acetic acid (12.7 mg) was added Intermediate 1.4 (20.8 mg) in DMF / DIPEA (0.5 mL, 5 / 1 ) and HOAT ( 8.17 mg) in DMF (0.5 mL), then Si-DCC (0.96 mmol / g, 180 mg) was added. The reaction mixture was stirred at 40 °C for 24 h. Add PL-HCO 3 (2.06mmol / g, 120mg) and PL-DETA (7.99mmol / g, 23mg) and the reaction mixture was stirred for another 3h. The resin was filtered, washed five times with 1 mL DCM / MeOH 1:1, and the resulting solution was evaporated in vacuo. The residue was dissolved in DMSO / MeCN 1:4 (0.5 mL) and purified by preparative LC-MS (II) to give 14 mg of a white solid. LC-MS(A):t R =0.57min; [M+H] + :479.2.

[0863] Examples 9 to 13 were synthesized according to the procedure described in Example 8, starting from the appropriate acid derivative. LC-MS data for Examples 9 to 13 are list...

Embodiment 14

[0865] Example 14: 1-{4-[4-(1H-benzimidazol-2-yl)-thiazol-5-yl]-piperazin-1-yl}-2-imidazo[4,5-b] Pyridin-3-yl-ethanone:

[0866] 14.1. Imidazo[4,5-b]pyridin-3-yl-benzyl acetate:

[0867] To a brown solution of 4-azabenzimidazole (4.75 g) in DMF (80 mL) was added benzyl bromoacetate (6.58 mL) followed by Cs 2 CO 3 (25.9g). The resulting light brown suspension was stirred overnight. The reaction mixture was diluted with EA and washed with water and saturated NH 4 Cl aqueous solution was washed twice. The aqueous layer was extracted twice with EA. by MgSO 4 The combined organic layers were dried, filtered and evaporated under reduced pressure. By CC (Biotage, SNAP 100g cartridge, Solvent A:DCM; Solvent B:DCM / MeOH8:2; Gradient %B: 0 to 5% in 3CV, 5% in 5CV, 5 to 15% in 5CV, 3CV 15% B) Purification of the crude product gave 4.99 g of the desired compound as a yellow solid. LC-MS(C):t R =0.59min; [M+H] + :267.86.

[0868] 14.2. Imidazo[4,5-b]pyridin-3-yl-acetic acid:

...

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Abstract

The invention relates to compounds of formula (I), wherein ring A, X, (R1)n, R2, R3, R4, R4', R5, n, and p are as described in the description. The invention also relates to pharmaceutically acceptable salts thereof, and to the use of the compounds as medicaments, especially as modulators of the CXCR3 receptor.

Description

technical field [0001] The present invention relates to novel 4-(benzimidazol-2-yl)-thiazole compounds of formula (I) and related aza-derivatives, and their use as medicaments. The present invention also relates to related aspects including preparation methods of said compounds, pharmaceutical compositions containing one or more compounds of formula (I), especially their use as CXCR3 receptor modulators. Background technique [0002] Chemokine receptors are a class of G-protein coupled receptors (GPCRs) that bind peptide chemokine ligands with high affinity. The primary function of chemokine receptors is to direct leukocyte trafficking to lymphoid organs and tissues at rest and during inflammatory responses, but the effects of some chemokine receptors on non-hematopoietic cells and their progenitors are also recognized. [0003] The chemokine receptor CXCR3 is associated with the inflammatory chemokines CXCL9 (originally MIG, interferon-γ [INF-γ]-inducible monokine), CXCL10...

Claims

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Application Information

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IPC IPC(8): C07D417/14C07D471/04C07D487/04C07D519/00A61K31/427
CPCC07D471/04C07D417/14C07D487/04C07D519/00A61P1/06A61P17/06A61P25/00A61P25/14A61P25/28A61P29/00A61P31/00A61P35/00A61P37/00A61P37/02A61P37/06A61P9/10A61P3/10A61K31/4184A61K31/427C07D235/04
Inventor 伊娃·卡罗夫马塞尔·凯勒蒂里·吉姆马林伊曼纽尔·梅耶
Owner IDORSIA PHARM LTD
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