Compound as Hedgehog path inhibitor, medicine composition containing same and application thereof

A technology for compounds and solvates, applied in the field of compounds and compositions containing the compounds, can solve problems such as insignificant therapeutic effects

Active Publication Date: 2011-03-30
BEIJING HANMI PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Feldmann et al. used an animal model to demonstrate that Hedgehog inhibitors combined with gemcitabine could inhibit the growth of pancreatic cancer, whereas neither gemcitabine nor hedgehog inhibitors had significant therapeutic effects alone

Method used

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  • Compound as Hedgehog path inhibitor, medicine composition containing same and application thereof
  • Compound as Hedgehog path inhibitor, medicine composition containing same and application thereof
  • Compound as Hedgehog path inhibitor, medicine composition containing same and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment

[0168] The experiments, synthesis methods and intermediates described below are illustrative of the present invention and do not limit the scope of the present invention.

[0169] The starting materials used in the experiments in the present invention were either purchased from reagent suppliers or prepared from known materials by standard methods. Unless otherwise stated, the examples herein apply the following conditions:

[0170] 1) The unit of temperature is Celsius (°C); the definition of room temperature is 18-25°C;

[0171] 2) Dry the organic solvent with anhydrous magnesium sulfate or anhydrous sodium sulfate; use a rotary evaporator to spin dry under reduced pressure and elevated temperature (for example: 15mmHg, 30°C);

[0172] 3) Silica gel is used as a carrier during column chromatography separation, and TLC indicates a silica gel thin-layer plate;

[0173] 4) Usually, the progress of the reaction is monitored by TLC or LC-MS;

[0174] 5) Identification of the f...

preparation Embodiment 1

[0175] Preparation Example 1: N-{2-Methyl-3-[4'-(trifluoromethyl)phenyl]}phenyl-6-morpholine nicotinamide Synthesis

[0176]

[0177] 1) 3-amino-2-methyl-4'-trifluoromethylbiphenyl of preparation formula 3:

[0178] Weigh 3-bromo-2-methylaniline (1.0g, 5.4mmol, compound of formula 1), 4-trifluoromethylphenylboronic acid (1.3g, 6.8mmol, compound of formula 2), bistriphenylphosphine dichloride Palladium chloride (0.4 g, 0.54 mmol) and sodium carbonate (1.7 g, 16.0 mmol) were placed in a microwave synthesis reaction tube under nitrogen protection, and heated to 120° C. for 30 min by microwave. After the reaction was completed, the insoluble matter was removed by filtration, the filtrate was diluted with water, extracted with ethyl acetate, the organic phase was washed with brine, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the crude product was purified by column chromatography (n-hexane:ethyl acetate 8:1) to obtain a yellow...

preparation Embodiment 2

[0189] Preparation Example 2: N-{2-methyl-3-[4'-(trifluoromethoxy)phenyl]}phenyl-6-[(2R,6S)-2,6-dimethylmorph Synthesis of Phylo]pyridazine-3-amides

[0190]

[0191] 1) N-(3-bromo-2-methylphenyl)-6-chloropyridazine-3-amide of formula 3:

[0192]Under ice bath, 3-bromo-2-methylaniline (372.1 mg, 2.0 mmol, compound of formula 1), 6-chloropyridazine-3-acid (317.1 mg, 2.0 mmol, compound of formula 2), 1-( 3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI, 766.8 mg, 4.0 mmol) was mixed and dissolved in 10 mL of pyridine, stirred at room temperature overnight, pyridine was removed under reduced pressure, and the residue was washed with ethyl acetate Dissolved, the organic phase was washed with water (3×5 mL), and dried over anhydrous sodium sulfate. It was filtered, concentrated, and purified by silica gel column chromatography (n-hexane:ethyl acetate 5:1) to obtain a white solid (265.0 mg, 40.6%, compound of formula 3).

[0193] 1 H-NMR (300MHz, CDCl 3 )δ: 9...

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Abstract

The invention provides a compound of general formula I as an inhibitor and a preparation method thereof. The compound is used for inhibiting a Hedgehog signal path and can provide a new medicine for clinic effective cancer resistance. The invention also provides a medicine composition as an inhibitor, which contains the compound I as an effective ingredient and can be used for inhibiting the Hedgehog signal path so as to resist cancer. In addition, the invention also provides an application of the compound in the preparation of the medicine for inhibiting the Hedgehog signal path.

Description

technical field [0001] The present invention relates to a compound, in particular to a compound as an inhibitor and to a composition comprising the compound (C07D 521 / 00). Background technique [0002] The hedgehog signaling pathway discovered in Drosophila in 1980 plays an important regulatory role in the process of cell proliferation, differentiation and determination of cell fate during animal embryogenesis. A properly functioning Hedgehog signaling pathway is necessary for the formation of vital organs such as the brain, limbs, lungs, skin, and prostate (Ingham PW & McMahon AP (2001) Genes & Development 15, 3059-3087). Although the level of the Hedgehog signaling pathway in adults is much lower than that in embryos, this pathway still plays a vital role in the proliferation and renewal of adult tissues. Stem cells are a kind of pluripotent cells with self-renewal ability, that is, stem cells maintain an undifferentiated state and have the ability to proliferate. Under a...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D213/82C07D413/04C07D401/04C07D487/08A61K31/5377A61K31/496A61K31/541A61K31/4439A61K31/551A61P35/00A61P35/02
CPCA61K31/541A61K31/496C07D401/14C07D487/08A61K31/4439A61K31/551C07D413/14C07D213/82C07D405/12C07D417/14A61K31/5377C07D401/12C07D401/04C07D413/04A61P35/00A61P35/02
Inventor 文圣焕张波杨军金孟燮许树森毕学智李建华
Owner BEIJING HANMI PHARMA CO LTD
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