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Histone deacetylase inhibitor containing alpha amino acid structure and application thereof

A technology of alkylamino and hydroxyl group, which is applied in the field of pharmaceutical preparations and achieves the effect of good development prospect and good selectivity

Inactive Publication Date: 2012-11-07
CHINA PHARM UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

(Paris M, Porcelloni M, Binaschi M, et al. Histone Deacetylase Inhibitors: From Bench to Clinic. Journal of Medicinal Chemistry, 2008, 51: 1505-1529.) The currently marketed HDACs inhibitor SAHA and most of the clinical research The new drugs are all hydroxamic acids, and most of these compounds are not selective for each subtype of HDACs

Method used

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  • Histone deacetylase inhibitor containing alpha amino acid structure and application thereof
  • Histone deacetylase inhibitor containing alpha amino acid structure and application thereof
  • Histone deacetylase inhibitor containing alpha amino acid structure and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0054]

[0055] Preparation of methyl 4-((2-(tert-butoxycarbonylamino)-3-(1H-indol-3-yl)propionamido)methyl)benzoate

[0056] Dissolve N-tert-butoxycarbonyl tryptophan (Boc-Trp-OH, 6.08g, 20.0mmol) in anhydrous dichloromethane (DCM, 100mL), and cool in an ice-salt bath until the temperature of the reaction solution drops to -15°C , add 1-hydroxybenzotriazole (HOBT, 3.24g, 24.0mmol) to the above solution, continue stirring for 15min, then add 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride (EDCHCl, 7.66 g, 40 mmol) and triethylamine (TEA, 12.5 mL, 90 mmol). Stirring was continued for 30 min before methyl p-aminomethylbenzoate (4.03 g, 20.0 mmol) was added. The mixture was quenched after stirring at room temperature for 8 h. The reaction solution was washed 3 times with 80 mL water, anhydrous Na 2 SO 4 dry. The solvent was evaporated to dryness, and ethyl acetate was recrystallized to obtain a white solid (7.3g, 81.8%); M.p.178-180°C; 1 H NMR (DMSO-d 6 )δ: 1...

Embodiment 2

[0058]

[0059] Preparation of methyl 4-((2amino-3-(1H-indol-3-yl)propionamide)methyl)benzoate

[0060] To 4-((2-(tert-butoxycarbonylamino)-3-(1H-indol-3-yl)propionamido)methyl)methyl benzoate (Example 1, 11.40g, 0.025mol ) into a mixture solution of methanol (25 mL) and ethyl acetate (25 mL) was slowly added dropwise with acetyl chloride (8 mL), and after the dropwise addition was completed, the temperature was raised to reflux for 2 h. Then the solvent and excess HCl were spin-dried under reduced pressure and then added 5% Na 2 CO 3 Aqueous solution (80 mL), followed by addition of ethyl acetate for extraction, washing, drying, and concentration gave a white solid (8.9 g, 91.8%). 1 HNMR (DMSO-d 6 )δ11.08(s, 1H, NH Indole ), 9.12(t, 1H, NH), 8.34(bs, 3H, NH+NH 2 ), 7.84 (d, 2H, J=8.4, ArH), 7.67 (d, 1H, J=7.8, ArH), 7.39 (d, 1H, J=8.1, ArH), 7.20 (d, 3H, ArH), 7.10(t, 1H, ArH), 7.01(t, 1H, ArH), 4.44-4.27(m, 2H, CH 2 NH), 4.05 (bs, 1H, CHα Trp), 3.40-3.20 (m, 2H, CH...

Embodiment 3

[0062]

[0063] A general procedure for introducing amide side chains using various acid chloride reagents: methyl 4-((2amino-3-(1H-indol-3-yl)propionamide)methyl)benzoate (Example 2, 1.0 eq ) and triethylamine (TEA, 2.0eq) in dichloromethane were added dropwise acid chloride (1.2eq) or sulfonyl chloride (1.2eq). The solution was stirred at room temperature until TLC showed the reaction was complete. The reaction solution was concentrated, added with water, extracted with ethyl acetate, and washed with brine. The organic layer was dried and concentrated under reduced pressure, and the obtained crude product was separated and purified by column chromatography.

[0064] A general procedure for introducing amide side chains using various carboxylic acid reagents: Add HOBT (1.5 eq) to various carboxylic acid reagents (1.2 eq) in dichloromethane, stir for 15 min in ice bath and then add EDCI (1.2 eq) and TEA (4.5 eq). Stirring was continued for 20 min before methyl 4-((2amino-3...

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Abstract

The invention relates to the field of pharmaceutical chemistry, in particular relates to a histone deacetylase inhibitor (I) containing an alpha amino acid structure and a preparation method thereof. The invention also discloses an intermediate (V). Ar, R1, L1, L2 and A are defined in the specification. A pharmacological experiment proves that the compound in the invention has a good inhibition effect on histone deacetylase, exhibits obvious selectivity on Class IHDACs, and has a good antiproliferative activity on tumor cell strains.

Description

technical field [0001] The invention relates to the field of medicinal chemistry, in particular to a class of histone deacetylase inhibitors with an alpha amino acid structure, a preparation method thereof, a pharmaceutical preparation containing the same and a medical application thereof. Background technique [0002] In the process of chromatin modification, histone acetyltransferases (HATs) and histone deacetylases (HDACs) which have opposite effects jointly regulate the expression of genes. Among them, HDACs catalyze the deacetylation of N-terminal lysine residues of histones, making histones positively charged, tightly combined with negatively charged DNA, chromosomal structure aggregation, transcription factors unable to access target DNA, and transcriptional repression (Bolden JE, Peart MJ, Johnstone RW. Anticancer activities of histone deacetylase inhibitors. Nat Rev Drug Discov, 2006, 5:769-84.). HDACs have become an ideal target for reversing the abnormal epigenet...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D209/20C07D401/12C07D213/82C07D277/82C07C237/42C07C231/12C07C237/12C07C237/20C07C237/10A61K31/4045A61K31/454A61K31/4439A61K31/5377A61K31/167A61K31/4406A61K31/404A61K31/428A61P35/00A61P35/02A61P25/28A61P25/16A61P25/00
Inventor 尤启冬俞丽琴陆慧林克江杨波
Owner CHINA PHARM UNIV
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