Piperidylpyrimidine derivatives as modulators of protein kinase inhibitors and of vascular endothelial growth factor receptor 2

a technology of vascular endothelial growth factor and piperidylpyrimidine, which is applied in the direction of biocide, organic chemistry, animal husbandry, etc., can solve the problems of abnormal blood vessel growth

Active Publication Date: 2016-04-14
ALLERGAN INC
View PDF1 Cites 2 Cited by
  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0169]The patient will be administered the compound orally in any acceptable form, such as a tablet, liquid, capsule, powder and the like, or other routes may be desirable or necessary, particularly if the patient suffers from nausea. Such other routes may include, without exception, transdermal, parenteral, subcutaneous, intranasal, via an implant stent, intrathecal, intravitreal, topical to the eye, back to the eye, intramuscular, intravenous, and intrarectal modes of delivery. Additionally, the formulations may be designed to delay release of the active compound over a given period of time, or to carefully control the amount of drug released at a given time during the course of therapy.

Problems solved by technology

In ophthalmic diseases such as neovascular age-related macular degeneration and diabetic retinopathy aberrant activation of VEGF receptors can lead to abnormal blood vessel growth.

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
  • Piperidylpyrimidine derivatives as modulators of protein kinase inhibitors and of vascular endothelial growth factor receptor 2
  • Piperidylpyrimidine derivatives as modulators of protein kinase inhibitors and of vascular endothelial growth factor receptor 2
  • Piperidylpyrimidine derivatives as modulators of protein kinase inhibitors and of vascular endothelial growth factor receptor 2

Examples

Experimental program
Comparison scheme
Effect test

example 1

[0221]

6-(Pyridin-3-ylcarbonyl)-N-(3,4,5-trimethoxyphenyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-amine

[0222]A solution of N-(3,4,5-Trimethoxyphenyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-amine, Intermediate 1 (75 mg, 0.24 mmol) in CH2Cl2 (1.5 mL) was cooled to 0° C. and treated with benzoic anhydride (56.7 mg, 0.251 mmol) and pyridine (22 microliter, 0.273 mmol). After 1 hour the reaction mixture was diluted with CH2Cl2 and washed with water. The organic phase was collected, dried and concentrated. The residue was purified by silica gel chromatography (15-40% acetone / CH2Cl2). The product containing fractions were concentrated to give the title compound (75 mg).

example 2

[0223]

N-phenyl-6-(pyridin-3-ylcarbonyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-amine

[0224]A solution of (2-chloro-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)(pyridin-3-yl)methanone, Intermediate 5 (0.025 g, 0.091 mmol) in isopropanol (0.1 mL) was treated with 3,4,5-trimethoxyaniline (0.021 g, 0.0498 mmol). The resulting mixture was heated to 60° C. and allowed to stir overnight. After being allowed to cool to room temperature EtOAc (10 mL) was added to the reaction mixture, and the resulting solution was then washed twice with brine (10 mL). The combined aqueous layers were washed once with EtOAc (10 mL). The organic layers were combined, then dried over anhydrous Na2SO4(s), filtered and concentrated in vacuo. The resulting crude residue was then purified over silica using a MeOH / CHCl3 gradient. The desired product was obtained in 54.8% yield (0.021 g, 0.049 mmol).

[0225]1H NMR (300 MHz, DMSO-d6) δ ppm 2.78-2.97 (m, 2H) 3.52-3.60 (m, 1H) 3.61 (s, 3H) 3.75 (s, 6H) 3.96 (m, 1H) 4.3...

example 3

2-anilino-N-pyridin-3-yl-7,8-dihydropyrido[4,3-d]pyrimidine-6(5H)-carboxamide

[0226]A solution of N-phenyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-amine, Intermediate 6 (75 mg, 0.33 mmol), 3-isocyanatopyridine (41.8 mg, 0.35 mmol) in CH2Cl2 (1.5 mL) was stirred at room temperature for 1 hour. After 1 hour the reaction mixture was diluted with CH2Cl2 and washed with sat. aqueous NaHCO3(aq). The organic phase was collected, dried and concentrated. The residue was dissolved in CH2Cl2 and washed with 3% aqueous LiCl solution and water. The organic phase was collected, dried and concentrated to give the title compound (45.9 mg).

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

PropertyMeasurementUnit
volumeaaaaaaaaaa
pHaaaaaaaaaa
pHaaaaaaaaaa
Login to view more

Abstract

This invention is directed to a compound of Formula Ior a pharmaceutically acceptable salt thereof, wherein X, R1, R2, R3, R4, R5, R6 and R7 are as defined herein. The compounds of Formula I are useful as protein kinase (PK) inhibitors and can be used to treat such diseases as cancer, blood vessel proliferative disorders, fibrotic disorders, mesangial cell proliferative disorders, metabolic diseases inflammatory disorders and neurodegenerative disorders.

Description

FIELD OF THE INVENTION[0001]The invention relates to inhibitors of vascular endothelial growth factor receptor 2 kinase (VEGFR2) or VEGFR, platelet derived growth factor beta (PDGFRβ) kinases or PDGFR and Protein Kinase R (EIF2AK2), and methods of using such compounds. The present invention is also directed to methods of regulating, modulating or inhibiting protein kinases, whether of the receptor or non-receptor class, for the prevention and / or treatment of disorders related to unregulated protein kinase signal transduction, including cell growth, metabolic, blood vessel proliferative, inflammatory and neurodegenerative disorders.DESCRIPTION OF THE RELATED ART[0002]Protein kinases (PKs) comprise a large and diverse class of proteins having enzymatic activity which catalyzes the transfer of the terminal phosphate of ATP to the hydroxyl group of a serine, threonine or tyrosine group in a protein. Protein kinases (PKs) are involved in numerous diseases which result from dysregulation ...

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): C07D471/04
CPCC07D471/04
Inventor WURSTER, JULIE A.MALONE, THOMAS C.HULL, III, CLARENCE EUGENERAO, SANDHYAYANG, RONGYEE, RICHARD
Owner ALLERGAN INC
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