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Quinazoline derivatives and their use as DNA methyltransferase inhibitors

An alkyl and aryl technology, applied in the field of quinazoline derivatives, can solve problems such as lack of specificity, low activity, and high toxicity

Inactive Publication Date: 2016-05-04
PIERRE FABRE MEDICAMENT SAS +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Many of them have been shown to target the catalytic site, but have high toxicity, lack of specificity and low activity

Method used

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  • Quinazoline derivatives and their use as DNA methyltransferase inhibitors
  • Quinazoline derivatives and their use as DNA methyltransferase inhibitors
  • Quinazoline derivatives and their use as DNA methyltransferase inhibitors

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0364] Example 1: Compound F

[0365]

[0366] a) i) SOCl 2 , 110°C, 1h.ii) Amphetamine, DMF, K 2 CO 3 ,RT,2h,85%.

[0367] 4-(3-phenylpropylamino)-7-(2-chloroethoxy)quinazoline (17)

[0368] A solution of 16 (440 mg; 2.01 mmol) in thionyl chloride (10 mL) and a catalytic amount of DMF was boiled for 30 min. The solvent was removed, and the crude product was dissolved in a DMF solution of amphetamine (570 μL; 4.0 mmol), and the mixture was stirred at room temperature for 2 h. The mixture was diluted with ethyl acetate and saturated Na 2 CO 3 solution, the organic phase was washed with brine, and dried over magnesium sulfate. The solvent was removed and the residue was purified by silica gel flash chromatography using a linear gradient of ethyl acetate in cyclohexane (0→100% ethyl acetate) to afford 17 as a pale brown solid (607 mg; 1.70 mmol; yield 85 %).

[0369]

[0370] 1 HNMR (500MHz, CDCl 3 )δ8.58 (s, 2H, Ha1), 7.35-7.13 (m, 7H, Ha7, Ha15, Ha13 and Ha14...

Embodiment 2

[0407] Example 2: Compounds A, B, C, D, E, T and U

[0408]

[0409] a) 3-Boc aminopropylamine or 4-Boc aminobutylamine, DMF, 125°C, 4h, 78% for n=1 and 73% for n=2. b) TFA, 91% for n=1 and 84% for n=2. c) NosCl, TEA, DMAPcat., DMF, RT, 6h, 66% for n=1 and 71% for n=2. d) i) 17, K 2 CO 3 , KIcat., DMF, RT, 80°C, 6h, 71% for n=1 and 75% for n=2.ii) PhSH, K 2 CO 3 , MeCN, RT, 24h, 85% for n=1 and 75% for n=2. e) TFA, water, RT, 1h. Or e) i) methyl 4-bromobutyrate, TEA, DMF, 90°C, 12h, 44% for n=1 and 45% for n=2. f) 0.5N NaOH, dioxane, 18h, 78% for n=1 and 79% for n=2.

[0410] 4-((2-Bocaminopropyl)amino)quinoline (27)

[0411] 4-((2-Bocaminobutyl)amino)quinoline (28)

[0412] N-boc aminopropylamine (2.06g, 11.84mmol) or N-boc aminobutylamine (2.25g, 12mmol), 4-chloroquinoline (1.525g, 9.32mmol) and DiPEA (1.8mL, 10.3mmol) in 12mL normal The solution in amyl alcohol was stirred at reflux for 6h. The solvent was removed and the residue was diluted in DCM. The organi...

Embodiment 3

[0487] Example 3: Compound G

[0488]

[0489] a) N-Boc-piperidine-4-methanol, NaH, DMF, 110℃, 3h, 67%. b) POCl 3 , Triazole, TEA, MeCN, RT, 18h. c) 3-amphetamine, TEA, DMF, RT, 2h, two steps 80%. d) TFA, RT, 1h, 96%. e) 26, K 2 CO 3 , KI, DMF, 65℃, 12h, 62%.

[0490] 7-O-((N-Boc)piperidin-4-ylmethoxy)quinazolinone (43)

[0491] To a mixture of (N-Boc)piperidin-4-ylmethanol (1.12 g; 5.2 mmol) in DMF (2 mL) was added sodium hydride (125 mg, 5.2 mmol) at 0 °C under argon. The mixture was stirred at 0 °C for 15 min, then 42 (162 mg; 1 mmol) was added portionwise. The mixture was stirred at 0 °C for 10 min, then at room temperature for 10 min, at 60 °C for 15 min, and finally at 110 °C for 2 h. The reaction mixture was diluted with ethyl acetate and washed with water and brine. The organic phase was dried over magnesium sulfate and the solvent was removed. The crude product was purified by flash chromatography on silica gel using a linear gradient of ethyl acetate in c...

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Abstract

The present invention relates to compounds of the following formula (I): and pharmaceutically acceptable salts and solvates thereof, their methods of preparation, their use as a drug, notably in the treatment of cancer, and pharmaceutical compositions containing such compounds.

Description

technical field [0001] The present invention relates to quinazoline derivatives useful as DNA methyltransferase (DNMT) inhibitors, especially in the treatment of cancer. Background technique [0002] Gene expression is known to be controlled by epigenetic modification. Methylation of deoxycytidine (dC) in DNA plays a key role in epigenetic regulation in mammals (Berger et al. GenesDev. 2009, 23, 781; Kelly et al. Biotechnol. 2010, 28, 1069). It is the most stable epigenetic mark and occurs at CpG sites that recombine in islands and are essentially located at promoters, repeats and CpG island shores (Gros et al. Biochimie 2012, 94, 2280). Hypermethylation of CpG islands of promoters induces gene silencing, whereas hypomethylation induces gene expression (Sharma et al. Carcinogenesis 2010, 31, 27; Esteller NEngl. J. Med. 2008, 358, 1148). [0003] The enzyme responsible for DNA methylation is DNA methyltransferase (DNMT). Two families of catalytically-active DNMTs have bee...

Claims

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Application Information

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IPC IPC(8): C07D401/14C07D401/12A61K31/517A61P35/00
CPCA61K31/517A61P35/00C07D401/12C07D401/14
Inventor L·阿尔比P·B·阿里蒙多
Owner PIERRE FABRE MEDICAMENT SAS
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