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Furo- and thieno [3,2-c] pyridines

A technology of -NR5 and -CF3, applied in the field of compounds that inhibit the activity of tyrosine kinases in animals, can solve problems such as affecting cell metabolism, reducing proliferation, and inducing apoptosis

Inactive Publication Date: 2011-04-06
OSI PHARMA INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Inhibition of RON has been shown to result in decreased proliferation, induce apoptosis, and affect cellular metabolism

Method used

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  • Furo- and thieno [3,2-c] pyridines
  • Furo- and thieno [3,2-c] pyridines
  • Furo- and thieno [3,2-c] pyridines

Examples

Experimental program
Comparison scheme
Effect test

preparation example Construction

[0124] Scheme 1 shows the preparation of intermediate 7.

[0125] Route 1

[0126]

[0127]Intermediate 2 can be prepared from 2-furfurfural in a well-known four-step process consisting of the Knoevenagel condensation method of malonic acid followed by decarboxylation, conversion of the resulting acid to its acyl azide, the azide Thermal rearrangement of the nitrogen compound gives the isopropionate and the thermal cyclization composition of the isopropionate. The synthetic routes of this furo[3,2-c]pyridine and thieno[3,2-c]pyridine have been disclosed in the literature, such as Ger.Offen.DE2059386 (1971), Ger.Offen.DE1965710 (1970) , US3663559 (1971) and WO2004 / 000828A1. Bromination agents including but not limited to NBS occur at the indicated positions to give intermediate 3, which is then further combined with POBr 3 Bromination affords intermediate 4. The corresponding thieno[3,2-c]pyridine can be prepared by the same method, such as US2005043347. Palladium-cata...

example

[0158] Shown below is the synthesis of various compounds of the invention. Other compounds within the scope of the present invention can be synthesized by the methods in the examples, and can also be synthesized together with the methods in the prior art.

[0159] The following abbreviations will be used.

[0160] NMR: nuclear magnetic resonance

[0161] MDPS: Mass guided HPLC purification system

[0162] MDP: mass-guided HPLC purification

[0163] LC / MS: Liquid Chromatography Mass Spectrometry

[0164] LDA: lithium diisopropylamide

[0165] DCM: dichloromethane

[0166] THF: Tetrahydrofuran

[0167] EtOAc: ethyl acetate

[0168] MeCN: Acetonitrile

[0169] DMSO: Dimethylsulfoxide

[0170] Boc: tert-butoxycarbonyl

[0171] DMF: N,N-Dimethylformamide

[0172] PS-DIEA: Polymer-supported diisopropylethylamine

[0173] PS-PPh3-Pd: polymer supported Pd(PPh3)4

[0174] EDCI or EDC: 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide

[0175] HOBt: 1-Hydroxybenzotriazole

[...

example 1

[0222] Example 1: 7-[(R)-1-(2,6-dichloro-3-fluorophenyl)-ethoxy]-furo[3,2-c]pyridin-6-ylamine

[0223]

[0224] 7-[(1R)-1-(2,6-Dichloro-3-fluorophenyl)ethoxy]-6-nitrofuro[3,2-c]pyridine (40 mg, 0.11 mmol) in EtOH (1 mL) solution was added iron powder (24 mg, 0.43 mmol) and 1M HCl (aq.) (0.05 mL, 0.05 mmol). The reaction mixture was stirred at 95°C for 20 minutes. After cooling to room temperature, the reaction mixture was passed through a pad of celite. The filtrate was concentrated in vacuo and the residue was purified by prep TLC (5% MeOH in DCM) to afford the title brown oil (25 mg, 68% yield). 1 H NMR (CDCl 3 , 400MHz): δ=1.86(d, J=6.60Hz, 3H), 4.75(br, s, 2H), 6.55(q, J=6.97Hz, 1H), 6.65(d, J=2.20Hz, 1H) , 7.04(t, J=8.43Hz, 1H), 7.27(dd, J=8.80, 4.77Hz, 1H), 7.39(d, J=2.20Hz, 1H), 8.05(s, 1H). MS (ES + ): m / z 341.03, 343.01 (100) [MH + ]. HPLC: t R = 2.77 min (ZQ3: Polarization - 5 min).

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Abstract

Furo[3,2-c]Pyridine and Thieno[3,2-c]pyridine compounds of Formula (I), and pharmaceutically acceptable salts thereof, preparation, intermediates, pharmaceutical compositions, and use, such as in disease treatment, including cancers, including conditions in which EMT is involved, including conditions mediated by protein kinase activity such as RON and / or MET.

Description

Background technique [0001] The present invention relates to furo[3,2-c]pyridine and thieno[3,2-c]pyridine compounds, their salts, compositions and therapeutic uses, in particular to inhibition of tyrosine kinase activity in animals (including humans) compounds, thereby preventing and / or treating various diseases and conditions, such as cancer. [0002] RON (Receptor Tyrosine Kinase) is a receptor tyrosine kinase that is part of the MET proto-oncogene family. RON is activated through the combination of PI3K and MAPK pathways and its natural ligand MSP and signaling. RON can be deregulated in cancer through mechanisms such as receptor overexpression and / or constitutively active splice variants. Inhibition of RON has been shown to result in decreased proliferation, induce apoptosis, and affect cellular metabolism. Overexpression of RON is observed in a variety of human cancers and shows increased expression as the disease progresses. [0003] MET is a receptor tyrosine kinas...

Claims

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Application Information

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IPC IPC(8): C07D491/048A61K31/4355A61P35/00
CPCC07D491/048A61P35/00A61P35/02A61P35/04A61P43/00
Inventor M·J·玛维海尔晶·王陈新王提李安户A·G·斯坦格A·克林伯格翁清华董汉卿金美中
Owner OSI PHARMA INC
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