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Pyridine-pyridinone derivatives, preparation and therapeutic use thereof

A compound and alkyl technology, applied in the field of pyridopyridone derivatives, can solve the problems such as chemotherapy can not achieve cure

Inactive Publication Date: 2012-10-31
SANOFI SA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Chemotherapy improves progression-free survival and overall survival, but does not achieve cure due to extreme heterogeneity of bone metastases within the same patient

Method used

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  • Pyridine-pyridinone derivatives, preparation and therapeutic use thereof
  • Pyridine-pyridinone derivatives, preparation and therapeutic use thereof
  • Pyridine-pyridinone derivatives, preparation and therapeutic use thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0290] Example 1: 2-{6-[7-Amino-8-ethyl-6-(1H-imidazol-2-yl)-5-oxo-5,8-dihydro-[1,8]naphthyridine-2 -yl]-pyridin-3-yl}-N-(pyridin-2-yl)-acetamide (compound 2)

[0291] 1.1 / 6-Chloro-2-(ethylamino)pyridine-3-carboxylic acid

[0292] A solution of 18.0 g (84.4 mmol) of 2,6-dichloropyridine-3-carboxylic acid in 180 ml (3.45 mol) of 70% aqueous ethylamine was heated at 50° C. for 10 hours. The excess amine was then evaporated under reduced pressure, followed by the addition of 10% aqueous acetic acid until the product precipitated. The beige solid was filtered, rinsed with cold water and dried. 10.5 g of the desired product are obtained. Yield = 62%. Melting point: 158-160°C. M H + : 201.1 (Tr: 7.7 minutes, condition 1).

[0293] 1.2 / 6-Chloro-2-(ethylamino)pyridine-3-carbonyl fluoride

[0294] 4.2 ml (52.3 mmol) of pyridine and 8.4 ml (99.6 mmol) of cyanuric fluoride were added successively to a suspension of 10.5 g (52.3 mmol) of the compound obtained in step 1.1 i...

Embodiment 2

[0307] Example 2 : 2-{4-[7-amino-8-ethyl-6-(1H-imidazol-2-yl)-5-oxo-5,8-dihydro-[1,8]phthalazine- 2-yl]-phenyl}-N-(4-cyclopropyl-morpholin-3-ylmethyl)-acetamide (compound 3)

[0308] 2.1 / Ethyl [4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]acetate

[0309] A mixture of 9.5 g (33 mmol) (4-iodo-phenyl)-ethyl acetate and 9.2 g (36 mmol) dipinacol diboronate in anhydrous dimethylsulfoxide (65 ml) was degassed with argon After 15 minutes, 28 g (98 mmol) of potassium acetate and 1.34 g (1.6 mmol) of (phosphinoferrocene)palladium dichloride were added and the reaction mixture was heated at 55° C. under argon for 1.5 hours. The reaction mixture was diluted with 220ml ethyl acetate, then the organic phase was washed three times with water (200ml), then washed with Na 2 SO 4 Dry and concentrate under reduced pressure. 11 g of compound was obtained as a brown oil and used as such in the next step. MH + : 291.2 (Tr: 9.4 minutes, condition 1).

[0310] 2.2 / (4-{7-amin...

Embodiment 3

[0321] Example 3 : 2-{4-[7-amino-8-ethyl-6-(1H-imidazol-2-yl)-5-oxo-5,8-dihydro-[1,8]phthalazine- 2-yl]-phenyl}-N-(pyridin-4-ylmethyl)-propionamide (compound 47)

[0322] 3.1 / 2-[4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]propanoic acid ethyl ester

[0323] The same operation as described in step 2.1 of Example 2, from a solution of 0.6g (2mmol) ethyl 2-(4-iodophenyl) propionate in anhydrous DMSO (4ml), 0.57g (2.2mmol) diboronic acid Start with dipinacol ester, 1.7 g (6 mmol) potassium acetate and 83 mg (0.1 mmol) (phosphinoferrocene)palladium dichloride. Obtained 0.9 g of compound as a brown oil and used as such in the next step. MH + : 305 (Tr: 9.9 minutes, condition 1).

[0324] 3.2 / 2-{4-[7-Amino-8-ethyl-5-oxo-6-(1-{[2-(trimethylsilyl)ethoxy]methyl Base}-1H-imidazol-2-yl)-5,8-dihydro-1,8-naphthyridine-2-yl]phenyl}propionic acid

[0325] The same operation as described in Example 2 step 2.2, from 0.57g (1.4mmol) of the compound obtained in step 3.1, ...

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Abstract

The invention relates (i) to pyridine-pyridinone derivatives with the formula (I): where R1 is a hydrogen atom or a (C1-C4)alkyl group; R2 is a (CH2)n-B group, in which n' = 0, 1, 2, 3 or 4 and B is a (C3-C5)cycloalkyl group, a (C1-C4)alkyl group or a (C1-C4)alkoxy group; Y, Z, V and W are, independently from one another, a -CH- group, a carbon atom, a heteroatom or no atom, with the understanding that the cycle, which includes V, W, Y and Z, is a cycle including 5 or 6 members, with the understanding that the dotted lines in said cycle indicate that the resulting cycle is an aromatic cycle and with the understanding that said cycle includes 0, 1 or 2 heteroatoms; R3 and R4 are, independently from one another, identical or different groups selected among a hydrogen atom and a straight (C1-C4)alkyl group, or form a (C3-C5)cycloalkyl group together with the carbon to which the former are bonded; m is an integer equal to 1, 2, 3 or 4; R5 is a hydrogen atom or a (C1-C4)alkyl group; R6 is a (CH2)n-L group where n = 0, 1, 2 or 3, and L is a group selected among aryls with 6 carbon atoms, heteroaryls having 5 or 6 members, the saturated heterocycles including 5, 6 or 7 members or forming a heterocycle group together with the nitrogen atom to which the former are linked. The invention also relates (ii) to the preparation of said derivatives, and (iii) to the therapeutic use thereof as inhibitors of kinase activity in receptors having PDGF ligands and / or receptors with the FLT3 ligand.

Description

technical field [0001] The present invention relates to pyridopyridone derivatives which are (i) substituted at the 3-position by an imidazole which itself is substituted by a group R1, and (ii) substituted at the 7-position by an aryl or heteroaryl group which The radical or heteroaryl itself is optionally of the type -[C(R3)(R4)] m Unit substitution of -CO-N(R5)(R6). The invention also relates to the preparation of said derivatives and said derivatives as inhibitors of the kinase activity of PDGF (platelet-derived growth factor) ligand receptors and optionally as FLT3 (fms-like tyrosine kinase receptor) ligands Therapeutic use of inhibitors of kinase activity of receptors. Background technique [0002] The FLT3 receptor and the PDGF-R receptor are members of the type III tyrosine kinase receptor (TKR) family, which also includes the stem cell factor (c-kit) receptor and the M-CSF (c-fms) receptor. body. They are characterized by an extracellular domain consisting of fi...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D471/04A61K31/4375A61P35/00
CPCC07D471/04A61P13/12A61P17/00A61P17/06A61P19/04A61P27/02A61P35/00A61P35/02A61P35/04A61P37/00A61P37/06A61P43/00A61P7/02A61P9/00A61P9/04A61P9/08A61P9/10A61P9/12A61P3/10A61K31/4375
Inventor G.拉萨尔V.马丁G.麦科特C.沃尔-查利尔
Owner SANOFI SA
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