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Pyrrolo[3,2-c]pyridine-6-amino derivatives

A 2-c, pyrrole technology, applied in drug combination, organic chemistry, pharmaceutical formulation, etc.

Active Publication Date: 2020-11-13
CANCER RES TECH LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In particular, there is a need for compounds that are potent inhibitors of Mps1 activity that are potent but also have low toxicity; good stability in human liver microsomes and good PK profiles (especially low clearance levels)

Method used

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  • Pyrrolo[3,2-c]pyridine-6-amino derivatives
  • Pyrrolo[3,2-c]pyridine-6-amino derivatives
  • Pyrrolo[3,2-c]pyridine-6-amino derivatives

Examples

Experimental program
Comparison scheme
Effect test

Embodiment

[0161] General experiment

[0162] Commercially available starting materials, reagents and dry solvents were used as provided.

[0163] Flash column chromatography was performed using Merck silica gel 60 (0.025mm-0.04mm). Column chromatography was also performed on the FlashMaster Personal Unit using isolute Flash silica columns or the Biotage SP1 purification system using Merck or Biotage flash silica cartridges.

[0164] Preparative TLC was performed on Analtech or Merck plates. Ion exchange chromatography uses acidic Isolute FlashSCX-II column, Isolute Si-carbonate column or basic isolute Flash NH 2 column carried out. Preparative HPLC uses a Phenomenex Luna column (5 μm, 250x 21.2mm, C18, Phenomenex, Torrance, USA) using a Gilson GX-281 liquid handler system in conjunction with a Gilson 322 HPLC pump (Gilson, Middleton, USA) from 10:90 to 100: 0 methanol:water (both modified with 0.1% formic acid) with a 15-minute gradient elution (Grad15mins20mls.m) at a flow rate of ...

Embodiment 2

[0177] Example 2-isopropyl 6-(2-methoxy-4-(1-methyl-1H-tetrazol-5-yl)phenylamino)-2-(1-methyl- Synthesis of 1H-pyrazol-4-yl)-1H-pyrrolo[3,2-c]pyridine-1-carboxylate

[0178] Synthesis of 3-methoxy-N-methyl-4-nitrobenzamide

[0179]

[0180] HATU (0.501 g, 1.319 mmol) was added to a solution of 3-methoxy-4-nitrobenzoic acid (0.2 g, 1.014 mmol), DIPEA (0.265 mL, 1.522 mmol) and 2M methylamine in THF (1.0 mL, 2.029 mmol) in THF (2.7 mL). The reaction mixture was stirred overnight at rt. It was then concentrated under reduced pressure and purified by Biotage column chromatography (DCM / EtOAc 80 / 20 to 60 / 40; 25g column) and subsequently (cyclohexane / EtOAc 50 / 50 to 40 / 60, 25g column) to give The title compound as a white solid (166 mg, 78%). 1 H NMR (500MHz, CDCl 3 ): δ3.07(d, J=4.9 Hz, 3H), 4.04(s, 3H), 6.27(app s, 1H), 7.28(dd, J=8.3, 1.6Hz, 1H), 7.64(d, J = 1.6Hz, 1H), 7.88 (d, J = 8.3Hz, 1H); LC (method B)-MS (ESI, m / z) t R 2.04 min,211[(M+H + ), 100%].

[0181] S...

Embodiment 3

[0190] Example 3 - Biological Activity

[0191] The following biological assays can be used to measure the pharmacological effects of the compounds of the invention.

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Abstract

The present invention relates to novel pyrrolo[3,2-c]pyridine-6-amino derivatives that inhibit the spindle checkpoint function of Monospindle 1 (Monospindle 1, Mps1 - also known as TTK) kinase. Specifically, the present invention relates to isopropyl 6-(2-methoxy-4-(1-methyl-1H-1,2,3-triazol-5-yl)phenylamino)-2-(1 ‑Methyl‑1H‑pyrazole‑4‑yl)‑1H‑pyrrolo[3,2‑c]pyridine‑1‑carboxylate and isopropyl 6‑(2‑methoxy‑4‑(1‑ Methyl-1H-tetrazol-5-yl)phenylamino)-2-(1-methyl-1H-pyrazole-4-yl)-1H-pyrrolo[3,2-c]pyridine-1- Carboxylic acid esters and their use as therapeutic agents for the treatment and / or prevention of proliferative diseases such as cancer. The invention also relates to processes for the preparation of these compounds and pharmaceutical compositions containing them.

Description

[0001] introduction [0002] The present invention relates to certain novel pyrrolo[3,2-c]pyridine-6-amino derivatives that act as inhibitors of the kinase activity of monopolar spindle 1 (Mps1 - also known as TTK). In particular, the present invention relates to novel pyrrolo[3,2-c]pyridine-6-amino derivatives per se, their use in the treatment and / or prevention of proliferative diseases such as, for example, cancer, processes for the preparation of these derivatives Methods and pharmaceutical compositions comprising them. [0003] Background of the invention [0004] Cancer arises from uncontrolled and unregulated cell proliferation. Precisely, what causes cells to become malignant and proliferate in an uncontrolled and unregulated manner has been the focus of intensive research in recent decades. This research has led to the targeting of surveillance mechanisms with anticancer agents, such as those responsible for regulating the cell cycle. [0005] The main roles of the ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D471/04A61K31/437A61P35/00
CPCA61P35/00C07D471/04
Inventor S·G·A·瑙德J·布拉格
Owner CANCER RES TECH LTD