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Substituted nicotinamide derivatives as kinase inhibitors

a technology of nicotinamide and derivatives, which is applied in the direction of drug compositions, immunological disorders, metabolism disorders, etc., can solve the problems of abnormal blood vessel growth, malignant tumor growth, or defects in key developmental processes, and achieve the effect of modulating, regulating and/or inhibiting tyrosine kinase signal transduction

Inactive Publication Date: 2015-06-18
ALLERGAN INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

This patent describes compounds that can treat diseases related to unregulated Tyrosine kinase signal transduction, such as cancer, blood vessel proliferative disorders, fibrotic disorders, and neurodegenerative diseases. Specifically, these compounds can be used to treat mesangial cell proliferative disorders, metabolic diseases, pterygium, arthritis, restenosis, hepatic cirrhosis, atherosclerosis, psoriasis, rosacea, diabetes mellitus, wound healing, and neurodegenerative diseases including ophthalmic diseases like diabetic retinopathy and age-related macular degeneration. Additionally, these compounds can also be used to treat dermatological indications like sun burn, eczema, and contact dermatitis.

Problems solved by technology

Aberrant expression or mutations in the PTKs have been shown to lead to either uncontrolled cell proliferation (e.g. malignant tumor growth) or to defects in key developmental processes.
In ophthalmic diseases such as exudative age-related macular degeneration and diabetic retinopathy aberrant activation of VEGF receptors can lead to abnormal blood vessel growth.

Method used

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  • Substituted nicotinamide derivatives as kinase inhibitors
  • Substituted nicotinamide derivatives as kinase inhibitors
  • Substituted nicotinamide derivatives as kinase inhibitors

Examples

Experimental program
Comparison scheme
Effect test

preparation 1

[0068]

tert-Butyl thiomorpholine-4-carboxylate

[0069]To a solution of thiomorpholine (4.84 mL, 50 mmol, 1 eq) in DCM (200 mL) was added Et3N (14.6 mL, 2.1 eq) and di-tert-butyldicarbonate (12.0 g, 1.1 eq) with stirring under nitrogen atmosphere. The resulting clear solution was stirred at RT for an overnight. The reaction solution was washed with H2O (1×), aqueous NH4Cl (1×), brine (1×) and dried over anhydrous MgSO4. The organic solution was filtered through a pad of celite and the filtrate concentrated. The white solid residue was treated with EtOAc-hexane (1:25) with stirring and then cooled in fridge for 30 min. The white solid which formed was collected to give the title compound as a white crystalline solid (10.1 g, quantitative). 1H NMR (DMSO-d6) δ: 3.54-3.59 (m, 4H), 2.48-2.54 (m, 4H), 1.40 (s, 9H)

preparation 2

[0070]

tert-Butyl thiomorpholine-4-carboxylate 1-oxide

[0071]In a 250 mL round-bottom flask equipped with a magnetic stirrer were placed powdered sodium metaperiodate (5.68 g, 1.05 eq) and water (50 mL). The mixture was stirred at RT first and then cooled to 0° C., followed by the addition of tert-butyl thiomorpholine-4-carboxylate (5.08 g, 25 mmol, 1 eq). Then to this mixture was added dixane (30 mL) and MeOH (40 mL). The reaction mixture was stirred at 0° C. for 5.5 hours. It was then filtered through a Buchner funnel, the white solid was washed with CHCl3 (3λ50 mL), and the resulting water-chloroform filtrate was transferred into a separation funnel. The lower chloroform was removed and the aqueous layer was extracted with CHCl3 (3×150 mL). The organic phases were combined and dried over anhydrous Na2SO4 overnight. The upper clear layer was then decanted and concentrated to give the title compound as white solid (5.41 g, 99%). 1H NMR (DMSO-d6) δ: 3.81 (d, J=13.4 Hz, 2H), 3.60 (br. ...

preparation 3

[0072]

tert-Butyl 1-imino-1λ4,4-thiazinane-4-carboxylate 1-oxide

[0073]Trifluoroacetamide (5.82 g, 2 eq), magnesium oxide (4.05 g, 4 eq), and rhodium(II) acetate dimer (330 mg, 0.03 eq) were placed in a 250 mL round bottom flask. Dichloromethane (70 mL) under a nitrogen atmosphere was then added with stirring, followed by the addition of tert-butyl thiomorpholine-4-carboxylate 1-oxide (5.41 g, 1 eq) and diacetoxyiodobenzene (12.1 g, 1.5 eq). The reaction mixture was stirred at RT overnight. Then it was filtered through a pad of celite and silica gel, washed with DCM first then with EtOAc. The filtrate was concentrated and the resulting oily residue was taken up in MeOH (250 mL), to which was added potassium carbonate (17.3 g, 5 eq). The reaction mixture was stirred at RT for 2 hours and filtered through a pad of celite and silica gel and washed with MeOH. The filtrate was concentrated under reduced pressure and the resulting lightly brown oily residue was treated with EtOAc with stirr...

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Abstract

The present invention relates to organic molecules capable of modulating tyrosine kinase signal transduction in order to regulate, modulate and / or inhibit abnormal cell proliferation.

Description

CROSS REFERENCE TO RELATED APPLICATIONS[0001]This application claims priority to and the benefit of U.S. Provisional Patent Application Nos. 61 / 915,186 and 61 / 915,209, each filed Dec. 12, 2013, the disclosures of which are hereby incorporated by reference in their entireties.BACKGROUND OF THE INVENTION[0002]1. Field of the Invention[0003]The present invention relates to novel compounds capable of modulating, regulating and / or inhibiting tyrosine kinase signal transduction. The present invention is also directed to methods of regulating, modulating or inhibiting tyrosine kinases, whether of the receptor or non-receptor class, for the prevention and / or treatment of disorders related to unregulated tyrosine kinase signal transduction, including cell growth, metabolic, and blood vessel proliferative disorders.[0004]2. Description of the Related Art[0005]Protein tyrosine kinases (PTKs) comprise a large and diverse class of proteins having enzymatic activity. The PTKs play an important ro...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): C07D411/14C07D405/14C07D213/82C07D405/12
CPCC07D411/14C07D213/82C07D405/14C07D405/12A61P1/16A61P3/00A61P3/10A61P9/00A61P9/10A61P13/12A61P17/00A61P17/02A61P17/06A61P19/02A61P25/28A61P27/02A61P27/10A61P35/00A61P37/06A61P43/00C07D411/12C07D413/14
Inventor BORAL, SOUGATOWANG, SHIMIAOMALONE, THOMASWURSTER, JULIESHEN, JIEROBINSON, MICHAEL
Owner ALLERGAN INC
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