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Quinazolinones as prolyl hydroxylase inhibitors

A quinazoline and pyrazole technology, applied in the field of quinazolinone compounds, can solve the problems of increased content and increased cell repopulation

Active Publication Date: 2012-03-21
JANSSEN PHARMA NV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Studies in animals have demonstrated that topical application of PDGF leads to increased wound DNA, protein, and hydroxyproline content; to thicker granulation and epidermal tissue formation; and to increased cellular repopulation at the wound site

Method used

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  • Quinazolinones as prolyl hydroxylase inhibitors
  • Quinazolinones as prolyl hydroxylase inhibitors
  • Quinazolinones as prolyl hydroxylase inhibitors

Examples

Experimental program
Comparison scheme
Effect test

example

[0150] Chemical analysis :

[0151] In obtaining the compounds and corresponding analytical data described in the Examples below, the following experimental and analytical protocols were followed unless otherwise indicated.

[0152] The reaction mixture was magnetically stirred at room temperature (rt) unless otherwise indicated. In cases where the solutions are "dried", they are usually 2 SO 4 or MgSO 4 Such as desiccant for drying. Where mixtures, solutions and extracts are "concentrated", they are usually concentrated under reduced pressure on a rotary evaporator.

[0153] Thin layer chromatography (TLC) was performed with Merck silica gel 60F 254 2.5cm×7.5cm 250μm or 5.0cm×10.0cm 250μm pre-coated silica gel plate. Preparative thin-layer chromatography was performed on EM Science silica gel 60 F 254 This was done on a 20cm x 20cm 0.5mm precoated panel with a 20cm x 4cm concentration zone.

[0154] Normal phase flash column chromatography (FCC) was performed on s...

example 1

[0159] Example 1: 1-(7-Chloro-4-oxo-3,4-dihydro-quinazolin-2-yl)-1H-pyrazole-4-carboxylic acid .

[0160]

[0161] Step A: Preparation of 7-Chloro-1H-quinazoline-2,4-dione. A mixture of 2-amino-4-chlorobenzoic acid (2.00 g, 11.6 mmol) and urea (2.80 g, 46.6 mmol) was heated to 200°C for 1 hour. The mixture was allowed to cool to room temperature and the resulting dough was thoroughly ground with water. The product was collected by filtration (2.30 g, 100%). MS and NMR data are consistent with those that have been described previously: Organic Process Research & Development, 2003, 7, 700-706. 1 H NMR (600MHz, DMSO-d 6 ): 12.00 (br s, 2H), 8.59-8.53 (m, 1H), 7.93-7.80 (m, 2H).

[0162] Step B: Preparation of 2,4,7-trichloroquinazoline. A mixture of 7-chloro-1H-quinazoline-2,4-dione (2.0 g, 10 mmol) was suspended in ACN (50 mL), then POCl was added 3 (5.0 mL, 55 mmol). Then DIEA (5.0 mL, 28 mmol) was added. The resulting mixture was heated to reflux for 36 hours, the...

example 2

[0168] Example 2: 1-(7-Trifluoromethyl-4-oxo-3,4-dihydro-quinazolin-2-yl)-1H-pyrazole-4- carboxylic acid .

[0169]

[0170] The title compound was prepared according to the method described in Example 1 using 2-amino-4-trifluoromethylbenzoic acid in Step A. MS (CI): C 13 h 7 f 3 N 4 o 3 The mass calculated value is 324.2; m / z measured value is 323.0 [M-H] - . 1 H NMR (400MHz, DMSO-d 6 ): 14.17-12.12 (br m, 2H), 8.98 (d, J = 0.6Hz, 1H), 8.32 (d, J = 8.3Hz, 1H), 8.29 (s, 1H), 8.02 (s, 1H), 7.80 (d, J=8.3Hz, 1H).

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Abstract

Quinazolinone compounds of formula (I) are described, which are useful as prolyl hydroxylase inhibitors. Such compounds may be used in pharmaceutical compositions and methods for the treatment of disease states, disorders, and conditions mediated by prolyl hydroxylase activity. Thus, the compounds may be administered to treat, e.g., anemia, vascular disorders, metabolic disorders, and wound healing.

Description

[0001] Cross references to related patent applications [0002] This patent application claims the benefit of US Provisional Patent Application Serial No. 61 / 151,429, filed February 10, 2009. technical field [0003] The present invention relates to certain quinazolinone compounds, pharmaceutical compositions containing such compounds and methods of using them to treat disease states, disorders and conditions mediated by prolyl hydroxylase activity. Background of the invention [0004] Cells respond to hypoxia by activating the transcription of genes involved in cell survival, oxygen delivery and utilization, angiogenesis, cell metabolism, blood pressure regulation, hematopoiesis, and tissue preservation. Hypoxia-inducible factor (HIF) is a key transcriptional regulator of these genes (Semenza et al., 1992, Mol Cell Biol., 12(12):5447-54; Wang et al., 1993, J Biol Chem., 268(29 ): 21513-18; Wang et al., 1993, Proc Natl Acad Sci., 90: 4304-08; Wang et al., 1995, J Biol Chem....

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D403/04A61K31/517A61P25/00
CPCC07D403/04A61P1/00A61P1/04A61P17/02A61P25/00A61P3/04A61P31/00A61P31/04A61P3/06A61P43/00A61P7/06A61P9/10A61P3/10
Inventor S·D·本贝内克F·M·霍库特B·E·小莱昂纳M·D·罗森K·T·塔兰蒂诺M·H·拉比诺维奇H·文卡特桑
Owner JANSSEN PHARMA NV
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