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Raf kinase inhibitors containing a zinc binding moiety

A technology of compounds, formulas, applied in the field of Raf kinase inhibitors containing zinc-binding moieties, which can solve the problems of difficulty, difficulty in regulatory approval of combination therapy, high cost of health care, etc.

Inactive Publication Date: 2010-03-17
CURIS INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

However, the effectiveness of this approach is often limited by the combined toxicity of the multiple agents due to off-target side effects and drug-drug interactions
Furthermore, combining compounds with different pharmacokinetics into a single dosage form is often difficult, and the attendant need to administer multiple drug treatments at different time intervals raises issues with patient compliance, thereby being able to destroy the efficacy of the drug combination
In addition, the health care costs of said combination therapy may be higher than that of single molecule therapy
In addition, obtaining regulatory approval for combination therapy may be more difficult because the burden of proving the activity / safety resulting from the combination of two agents is greater than that of a single agent (see Dancey J & Chen H 2006 in Nat. Rev .Drug Dis. Article published in Nature Reviews Drug Discovery 5:649)

Method used

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  • Raf kinase inhibitors containing a zinc binding moiety
  • Raf kinase inhibitors containing a zinc binding moiety
  • Raf kinase inhibitors containing a zinc binding moiety

Examples

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preparation example Construction

[0077] The preparation of pharmaceutical compositions containing active ingredients is well known in the art, for example, by mixing, granulating, or tablet-forming processes. The active therapeutic ingredient is usually mixed with excipients which are pharmaceutically acceptable and compatible with the active ingredient. For oral administration, the active agent is mixed with additives customary for the purpose, such as vehicles, stabilizers, or inert diluents, and converted by conventional methods into a suitable Forms for administration such as tablets, coated tablets, hard or soft gel capsules, aqueous, alcoholic or oily solutions and the like described in detail above.

[0078] The dose of the compound administered to the patient is lower than that which would induce toxicity in the patient. In certain embodiments, the dose of the compound administered to the patient is less than that which would result in the concentration of the compound in the patient's plasma at or a...

Embodiment 1

[0172] Example 1: (R)-4-(4-(3-(4-chloro-3-(trifluoromethyl)phenyl)urea Base) phenoxy) -N-(1-(hydroxylamino)-1-oxopropan-2-yl)pyridinecarboxamide (Compound 1) Preparation

[0173] Step 1a. Methyl 4-chloropicolinate (compound 102)

[0174] Anhydrous dimethylformamide (DMF) (10 mL) was slowly added to thionyl chloride (300 mL) at 40-48°C. The solution was stirred at room temperature for 10 minutes, and then compound 101 (100.0 g, 813.0 mmol) was added over a period of 30 minutes. The resulting solution was heated at 72°C (extensive sulfur dioxide evolution) for 16 hours, resulting in a yellow solid. The remaining mixture was cooled to room temperature, diluted with toluene (500 mL) and concentrated to 200 mL. The described toluene addition / concentration process was repeated twice. The above-obtained solution and the solid were added to 200 mL of methanol under an ice bath, keeping the internal temperature below 55°C. The contents were stirred at room temperature for 45 ...

Embodiment 2

[0192] Example 2: 4-(4-(3-(4-chloro-3-(trifluoromethyl)phenyl)ureido)benzene Oxy)-N-(3-(hydroxyamino)-3-oxopropyl)pyridinecarboxamide (compound 2) preparation of

[0193] Step 2a. Methyl 3-(4-(4-(3-(4-chloro-3-(trifluoromethyl)phenyl)ureido)phenoxy)pyridinecarboxamide)propanoate (compound 111-2 )

[0194] The title compound 111-2 was prepared from compound 110 (300.0 mg, 0.66 mmol) using a procedure similar to that described for the preparation of compound 111-1 (Example 1) (110 mg, 31% ): 537[M+1] + .

[0195] Step 2b. 4-(4-(3-(4-Chloro-3-(trifluoromethyl)phenyl)ureido)phenoxy)-N-(3-(hydroxyamino)-3-oxopropane base) pyridinecarboxamide (compound 2)

[0196] The title compound 2 is a solid (50 mg, 47 %): LCMS: 468 [M+1] + ; 1 H NMR (DMSO-d 6 ): δ2.25(t, J=6.9Hz, 2H), 3.47(m, 2H), 7.16(m, 3H), 7.38(d, J=2.4, 1H), 7.60-7.70(m, 4H), 8.15 (s, 1H), 8.50 (d, 1H), 8.78 (t, J=6.3Hz, 1H), 9.43 (s, 1H), 9.66 (s, 1H), 10.44 (s, 1H).

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Abstract

The present invention relates to Raf kinase inhibitors containing zinc-binding and their use in the treatment of Raf related diseases and disorders such as cancer. The said derivatives may further actas HDAC inhibitors.

Description

[0001] related application [0002] This application claims the benefit of US Provisional Application No. 60 / 895,910, filed March 20, 2007. The entire teachings of the aforementioned applications are incorporated herein by reference. Background technique [0003] Raf is a multigene family expressing oncogene protein kinases: A-Raf, B-Raf and C-Raf (also known as Raf-1), and isoform variants resulting from differential splicing of mRNA are known Known (see the article published by McCubrey, J A et al in 1998 in Leukemia "Leukemia" 12 (12): 1903-1929; Ikawa et al in 1988 in Mol.and Cell.Biol. "Molecular and Cellular Biochemistry Articles published in "8(6): 2651-2654; articles published by Sithanandam et al. in Oncogene "Oncogene" 5, 1775-1780 in 1990; articles published by Konishi et al. in Biochem.and Biophys.Res. Comm. Biochemical and Biophysical Research Letters 216(2):526-534). All three Raf kinases are functionally present in certain human hematopoietic cells, and their...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/506
CPCC07D213/81C07D213/64C07D213/75C07D213/63A61P35/00A61P35/02A61P43/00
Inventor 蔡雄钱长庚史蒂文·古尔德翟海啸
Owner CURIS INC
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