Methods of treatment of cell proliferative and/or ophthalmic diseases, disorders and conditions using inhibitors of protein tyrosine kinase activity

a technology of protein tyrosine kinase and inhibitors, which is applied in the field of compound medicines, can solve the problems of limiting this approach, affecting the effect of vegf inhibitors as cancer therapeutics, and vision loss, and achieves the effects of inhibiting kinase activity, and inhibiting protein tyrosine kinase activity

Inactive Publication Date: 2014-10-23
METHYLGENE
View PDF0 Cites 3 Cited by
  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The present invention provides new compounds and methods for treating diseases responsive to inhibition of kinase activity, particularly protein tyrosine kinase activity. The compounds are inhibitors of kinase activity and can be used as research tools to study the role of kinases in both normal and disease states. The invention also provides methods for inhibiting angiogenesis and treating cell proliferative and ophthalmic diseases by administering the compounds. The compounds can be used in the manufacture of medicaments for inhibiting kinase activity.

Problems solved by technology

Despite the attractiveness of anti-angiogenic therapy by VEGF inhibition alone, several issues may limit this approach.
VEGF expression levels can themselves be elevated by numerous diverse stimuli and perhaps most importantly, the hypoxic state of tumors resulting from VEGFr inhibition, can lead to the induction of factors that themselves promote tumor invasion and metastasis thus, potentially undermining the impact of VEGF inhibitors as cancer therapeutics.
The formation of new blood vessels is regulated by growth factors such as VEGF and HGF that activate receptor tyrosine kinases resulting in the initiation of signaling pathways leading to plasma leakage into the macula, causing vision loss.

Method used

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
View more

Image

Smart Image Click on the blue labels to locate them in the text.
Viewing Examples
Smart Image
  • Methods of treatment of cell proliferative and/or ophthalmic diseases, disorders and conditions using inhibitors of protein tyrosine kinase activity
  • Methods of treatment of cell proliferative and/or ophthalmic diseases, disorders and conditions using inhibitors of protein tyrosine kinase activity
  • Methods of treatment of cell proliferative and/or ophthalmic diseases, disorders and conditions using inhibitors of protein tyrosine kinase activity

Examples

Experimental program
Comparison scheme
Effect test

example 6

N-((6-(7-(4-(3-cyclopropylureido)-2-fluorophenoxy)thieno[3,2-b]pyridin-2-yl)pyridin-3-yl)methyl)-N-(2-methoxyethyl)formimidamide

[1029]A suspension of 1 (150 mg, 0.296 mmol) and ethylformimidate hydrochloride (130 mg, 1.18 mmol) in MeCNEtOH (10 mL / 5 mL) was heated to reflux overnight. More ethylformimidate hydrochloride (130 mg, 1.18 mmol), MeCN (20 mL) and EtOH (10 mL) were added, and the reaction mixture was heated to reflux overnight then cooled to RT. Finally the reaction mixture was concentrated and partitioned between AcOEt and water. The aqueous layer was concentrated (the desired compound is water-soluble at pH around 4-5). The residue was purified by Gilson (Phenomenex, Luna, 15μ, C18(2) 100A, 250×50.00 mm, 15 μm, 0.05% of formic acid in both MeOH / water: 20 / 80 to 95 / 5 over 60 min, flow=30 mL / min), to afford the title compound 7 (30 mg, 0.056 mmol, 23% yield) as a yellow-mustard solid. 1H NMR (400 MHz, DMSO-d6) δ (ppm): mixture of isomers and / or rotamers, 9.62-9.48 (m, 0.5H),...

example 7

1-cyclopropyl-3-(3-fluoro-4-(2-(5-(((2-methoxyethyl)(2,2,2-trifluoro ethyl)amino)-methyl)pyridin-2-yl)thieno[3,2-b]pyridin-7-yloxy)phenyl)urea

[1030]A solution of 1 (150 mg, 0.296 mmol), DIPEA (0.3 mL, 1.72 mmol) and 2-iodo-1,1,1-trifluoroethane (2 mL, 20.29 mmol) in DMSO (4 mL) was stirred at 110° C. overnight, then cooled to RT. The reaction mixture was partitioned between AcOEt and water. The organic layer was washed with a saturated aqueous solution of ammonium chloride, a saturated aqueous solution of sodium bicarbonate, dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified three times by Biotage (SNAP 12 g cartridge; MeOH / DCM: 00 / 100 to 10 / 90 over 20 CV, then 10 / 90 over 5 CV) and then by Gilson (Phenomenex, Luna 15μ C18(2) 100A, 250×50.00 mm, 15 μm, 0.05% formic acid in both MeOH / water: 60 / 40 to 95 / 5 over 60 min, flow=30 mL / min), to afford the title compound 8 (2.6 mg, 0.004 mmol, 2% yield) as a colorless sticky film. 1H NMR (400 MHz, MeCN-...

example 8

1-cyclopropyl-3-(3-fluoro-4-(2-(5-((2-hydroxyethylamino)methyl)pyridin-2-yl)-thieno[3,2-b]pyridin-7-yloxy)phenyl)urea

[1031]To a solution of 1 (400 mg, 0.788 mmol) in anhydrous DCM under nitrogen was slowly added BBr3 in DCM (6.3 mL, 1.0 M) at −50° C. The reaction mixture was allowed to warm to RT over 5 h. The reaction mixture was then quenched by addition of methanol and concentrated. The residue was dissolved in a mixture of methanol / 1N HCl / DMSO and purified twice by Gilson (Phenomenex, Luna, 15μ, C18(2) 100A, 250×50.00 mm, 15 μm, 0.05% of formic acid in both MeOH / water: 20 / 80 to 95 / 5 over 60 min, flow=30 mL / min), then (Phenomenex, Luna, 15μ, C18(2) 100A, 250×50.00 mm, 15 μm, 0.05% of formic acid in both MeOH / water: 20 / 80 to 70 / 30 over 60 min, flow=30 mL / min), to afford the title compound 9 (53 mg, 0.107 mmol, 15% yield, formate salt) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 9.12 (s, 1H), 8.60 (d, J=1.4 Hz, 1H), 8.52 (d, J=5.5 Hz, 1H), 8.32 (s, 1H), 8.30-8.21 (m, ...

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to view more

PUM

No PUM Login to view more

Abstract

This invention relates to methods for treating cell proliferative diseases and conditions and ophthalmic diseases, disorders and conditions using compounds that inhibit protein tyrosine kinase activity. In particular the invention relates to the methods of treatment which utilize compounds that inhibit the protein tyrosine kinase activity of growth factor receptors, resulting in the inhibition of receptor signaling, for example, the inhibition of VEGF receptor signaling.

Description

BACKGROUND OF THE INVENTION[0001]1. Field of the Invention[0002]This invention relates to compounds that inhibit protein tyrosine kinase activity. In particular the invention relates to compounds that inhibit the protein tyrosine kinase activity of growth factor receptors, resulting in the inhibition of receptor signaling, for example, the inhibition of VEGF receptor signaling and HGF receptor signaling. More particularly, the invention relates to compounds, compositions and methods for the inhibition of VEGF receptor signaling.[0003]2. Summary of the Related Art[0004]Tyrosine kinases may be classified as growth factor receptor (e.g. EGFR, PDGFR, FGFR and erbB2) or non-receptor (e.g. c-src and bcr-abl) kinases. The receptor type tyrosine kinases make up about 20 different subfamilies. The non-receptor type tyrosine kinases make up numerous subfamilies. These tyrosine kinases have diverse biological activity. Receptor tyrosine kinases are large enzymes that span the cell membrane and...

Claims

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to view more

Application Information

Patent Timeline
no application Login to view more
Patent Type & Authority Applications(United States)
IPC IPC(8): C07D495/04C07K5/06
CPCC07K5/06C07D495/04A61K38/005A61P9/10A61P27/02A61P35/00A61P43/00C07D519/00C07F9/6561A61K31/4365
Inventor RAEPPEL, STEPHANERAEPPEL, FRANCKCLARIDGE, STEPHEN WILLIAMZHAN, LIJIEGAUDETTE, FREDERICMANNION, MICHAELSATO, NORIFUMIYUKI, YOHEIKISHIDA, MASASHIVAISBURG, ARKADII
Owner METHYLGENE
Who we serve
  • R&D Engineer
  • R&D Manager
  • IP Professional
Why Eureka
  • Industry Leading Data Capabilities
  • Powerful AI technology
  • Patent DNA Extraction
Social media
Try Eureka
PatSnap group products

Browse by: Latest US Patents, China's latest patents, Technical Efficacy Thesaurus, Application Domain, Technology Topic.

© 2024 PatSnap. All rights reserved.Legal|Privacy policy|Modern Slavery Act Transparency Statement|Sitemap