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Barbiturate compound, preparing method and application thereof

A technology of barbituric acid and compounds, applied in the field of medicinal chemistry, can solve the problems that cannot be ruled out, the selectivity is not high, the inhibitory effect is not strong, etc., and the effect of good inhibitory activity can be achieved

Inactive Publication Date: 2016-05-04
CHINA PHARM UNIV +1
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

However, the possibility of interacting with other (even potentially undiscovered) LSD1 homologous enzymes or FAD-dependent enzymes cannot be ruled out. The potential toxicity of this covalent binding mechanism makes LSD1 irreversible inhibitors more risky
Reversible LSD1 inhibitors include peptides, polyamines and other small molecule compounds (ExpertOpin.Ther.Targets, 2012, 16, 1239-1249), but have weak inhibitory effect, low selectivity and specificity for LSD1 Issues such as weak sex

Method used

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  • Barbiturate compound, preparing method and application thereof
  • Barbiturate compound, preparing method and application thereof
  • Barbiturate compound, preparing method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0036] (E / Z)-5-((1H-indol-2-yl)methylene)-1-(4-bromophenyl)pyrimidine-2,4,6(1H,3H,5H)-trione Preparation of (I-1)

[0037] (1) Indole-2-carbaldehyde

[0038]

[0039]Add 805.8 mg (5 mmol) of indole-2-carboxylic acid to a 100 mL eggplant-shaped bottle, and add THF 30 mL. Slowly add LiAlH while stirring in an ice bath 4 379.5 mg (10 mmol). Stir at room temperature for 14 h until the end of the reaction detected by TLC. Add saturated NH 4 Cl solution, and the organic layer was extracted three times with ethyl acetate. Wash with brine, combine the organic layers, and dry over anhydrous sodium sulfate. The solvent was spin-dried under reduced pressure to obtain 441.5 mg of yellow crude indole-2-methanol, with a yield of 60%. The next reaction was carried out directly without purification.

[0040] Crude indole-2-methanol 441.5mg (3mmol) was dissolved in 20mLCH 2 Cl 2 , adding activated MnO 2 1.74g (20mmol), stirred at room temperature for 18h until the end of the reac...

Embodiment 2

[0051] (E / Z)-5-((1H-indol-2-yl)methylene)-1-(4-chlorophenyl)pyrimidine-2,4,6(1H,3H,5H)-trione Preparation of (I-2)

[0052] (1) 1-(4-Chlorophenyl)urea

[0053]

[0054] Referring to Example 1, 1-(4-chlorophenyl)urea was synthesized using p-chloroaniline as a raw material with a yield of 72.3%. 1 HNMR (300MHz, DMSO-d 6 )δ8.78(s, 1H, -N H -), 7.71 (d, J=8.4Hz, 2H, Ar H ), 7.38 (d, J=8.4Hz, 2H, Ar H ), 5.93(s, 2H, -N H 2 ).

[0055] (3) 1-(4-Chlorophenyl)pyrimidine-2,4,6(1H,3H,5H)-trione

[0056]

[0057] Reference Example 1, using 1-(4-chlorophenyl)urea as raw material to synthesize 1-(4-chlorophenyl)pyrimidine-2,4,6(1H,3H,5H)-trione with a yield of 52.0% . 1 HNMR (300MHz, DMSO-d 6 )δ11.51(s, 1H, -N H -), 7.54 (d, J=8.4Hz, 2H, Ar H ), 7.09 (d, J=8.4Hz, 2H, Ar H ), 3.72(s, 2H, -C H 2 -).

[0058] (4) (E / Z)-5-((1H-indol-2-yl)methylene)-1-(4-chlorophenyl)pyrimidine-2,4,6(1H,3H,5H) - Triketone (I-2)

[0059]

[0060] Referring to Example 1, using 1-(4-chl...

Embodiment 3

[0062] (E / Z)-5-((1Hindol-2-yl)methylene)-1-(3-nitrophenyl)pyrimidine-2,4,6(1H,3H,5H)-trione Preparation of (I-3)

[0063] (1) 1-(3-nitrophenyl)urea

[0064]

[0065] Referring to Example 1, 1-(3-nitrophenyl)urea was synthesized from m-nitroaniline with a yield of 63.0%. 1 HNMR (300MHz, DMSO-d 6 )δ8.91(s, 1H, -N H -), 8.35(s, 1H, Ar H ), 7.95 (m, 2H, Ar H ), 7.59(t, J=8.4Hz, 1H, Ar H ), 5.90(s, 2H, -N H 2 ).

[0066] (3) 1-(3-nitrophenyl)pyrimidine-2,4,6(1H,3H,5H)-trione

[0067]

[0068] Reference Example 1, using 1-(3-nitrophenyl)urea as raw material to synthesize 1-(3-nitrophenyl)pyrimidine-2,4,6(1H,3H,5H)-trione, yield 50.2%. 1 HNMR (300MHz, DMSO-d 6 )δ11.61(s, 1H, -N H -), 8.29 (d, J=6.8Hz, 1H, Ar H ), 8.2 (s, 1H, Ar H ), 7.82-7.75 (m, 2H, Ar H ), 3.76(s, 2H, -C H 2 -).

[0069] (4) (E / Z)-5-((1H-indol-2-yl)methylene)-1-(3-nitrophenyl)pyrimidine-2,4,6(1H,3H,5H )-triketone (I-3)

[0070]

[0071] Referring to Example 1, 1-(3-nitrophenyl)pyrimidine...

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Abstract

The invention belongs to the field of medicinal chemistry, and discloses a barbiturate compound, a preparing method and application thereof. Specifically, the invention relates to the compound as shown in formula I, and a medicinal usage thereof as a selective LSD1 reversible inhibitor, particular to the application in preparing of antitumor medicine. A test shows that the compound in formula I can efficiently reversibly inhibit LSD1 activity, and has a weak inhibition action for homologous proteins MAO-A and MAO-B, can intensively induce differentiation of leukemia cell NB4 and obviously enhance the methylation level of primers H3K4me1 and H3K4me2 of the LSD1.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry, and in particular relates to barbituric acid compounds, preparation methods and their medical use as histone lysine specific demethylase 1 inhibitors, especially the application in the preparation of antitumor drugs . Background technique [0002] A large number of studies have shown that the occurrence and development of tumors are not only related to genetic mutations, but also closely related to epigenetic regulation. In 2004, Shi Yang's group at Harvard University discovered the first histone lysine-specific demethylase 1 (Lysine Specific Demethylase1, LSD1), and for the first time clarified the dynamics between methylation and demethylation of histones The balance is regulated by histone methyltransferase and histone demethylase, respectively. This discovery opened up a new field of histone modification mechanism and drug research (Cell, 2004, 119, 941-953). LSD1 is a flavin adenine dinu...

Claims

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Application Information

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IPC IPC(8): C07D403/06C07D239/62C07D405/06C07D239/66A61P35/00A61P25/00A61P31/12A61P35/02
CPCC07D403/06C07D239/62C07D239/66C07D405/06
Inventor 查晓明蓝斐徐思远周忱徐云根
Owner CHINA PHARM UNIV
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