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PARP (poly-ADP-ribose polymerase)-1 and PI3K (phosphatidylinositol-3-kinase) dual target inhibitors containing phthalazine-1(2H)-ketone structure

A PARP-1, CH3 technology, applied in the fields of medical preparations containing active ingredients, organic chemistry, organic active ingredients, etc., can solve the problem of no dual-target inhibitor reports

Active Publication Date: 2019-05-28
CHINA PHARM UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

PI3K has become one of the important targets in tumor treatment research. Currently, there are two main PI3K inhibitors in clinical use, namely the PI3Kδ inhibitor Idelalisib, which was launched in 2014, and the PI3Kα / PI3Kδ inhibitor, which was launched in 2017. The drug Copanlisib is mainly used for the treatment of various lymphomas; in addition, there are still many PI3K inhibitors in the clinical research stage, but there is no report of PARP-1 / PI3K dual-target inhibitors

Method used

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  • PARP (poly-ADP-ribose polymerase)-1 and PI3K (phosphatidylinositol-3-kinase) dual target inhibitors containing phthalazine-1(2H)-ketone structure
  • PARP (poly-ADP-ribose polymerase)-1 and PI3K (phosphatidylinositol-3-kinase) dual target inhibitors containing phthalazine-1(2H)-ketone structure
  • PARP (poly-ADP-ribose polymerase)-1 and PI3K (phosphatidylinositol-3-kinase) dual target inhibitors containing phthalazine-1(2H)-ketone structure

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0065] 4-(3-(4-(4-(2-aminopyrimidin-5-yl)-6-morpholinyl-1,3,5-triazin-2-yl)piperazine-1-formyl)- Synthesis of 4-fluorobenzyl)phthalazin-1(2H)-one (I-1)

[0066] (2,6-dichloro-4-morpholinyl)-1,3,5-triazine (2)

[0067] Dissolve tripolychlorazine (1) (10.00g, 54.23mmol) in 100mL of dichloromethane, add DIEA (9.92mL, 56.94mmol), cool to -78°C, dissolve morpholine (4.73mL, 54.23mmol) The solution in 10mL of dichloromethane was added dropwise to the reaction solution. After the addition was complete, a large amount of white solids were precipitated. TLC (petroleum ether: ethyl acetate = 6:1) detected that the reaction of raw material 1 was completed, and the reaction was stopped. Suction filtration, the filter cake was water After washing and drying, 7.18 g of white solid was obtained, with a yield of 56.4%. 1 H NMR (300MHz, DMSO-d 6 )δ(ppm):3.80-3.76(4H,CH 2 O),3.69(4H,CH 2 ).

[0068] tert-butyl 4-(4-chloro-6-morpholinyl-1,3,5-triazin-2-yl)piperazine-1-carboxylate (3)

[0...

Embodiment 2

[0077] 4-(3-(4-(4-(6-aminopyridin-3-yl)-6-morpholinyl-1,3,5-triazin-2-yl)piperazine-1-formyl)- Synthesis of 4-fluorobenzyl)phthalazin-1(2H)-one (I-2)

[0078] With compound IV-1 (300mg, 0.53mmol) and 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-2- Amine (V-2) (128mg, 0.58mmol) was used as a raw material, and the operation was the same as that of I-1. It was separated by column chromatography (eluent: dichloromethane:methanol=80:1~30:1 gradient elution), and obtained shallow Yellow solid 160 mg, yield 48.5%. m.p.180-182℃. 1 HNMR (300MHz, DMSO-d 6 )δ (ppm): 12.61 (1H, s, CONH), 8.89 (1H, s, ArH), 8.26-8.19 (2H, m, ArH), 7.97-7.79 (3H, m, ArH), 7.46-7.37 ( 2H, m, ArH), 7.24 (1H, t, J=8.7Hz, ArH), 6.57 (2H, s, ArNH 2 ), 6.45 (1H, d, J=8.4Hz, ArH), 4.33 (2H, s, ArCH 2 ),3.93-3.64(14H,m,2CH 2 O,5CH 2 N),3.27-3.18(2H,m,CH 2 N). 13 C-NMR (75MHz, DMSO-d 6 )δ(ppm):168.62,164.31,163.98,161.91,159.34,154.76,149.69,144.82,136.66,134.76,133.44,131.49,129.05,127.88,126....

Embodiment 3

[0080] 4-(3-(4-(4-(6-Amino-4-(trifluoromethyl)pyridin-3-yl)-6-morpholinyl-1,3,5-triazin-2-yl) Synthesis of piperazine-1-formyl)-4-fluorobenzyl)phthalazin-1(2H)-one (I-3)

[0081] With compound IV-1 (300mg, 0.53mmol) and 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4-( Trifluoromethyl)pyridin-2-amine (V-3) (168mg, 0.58mmol) is raw material, operation is the same as I-1, column chromatography separates (eluent: dichloromethane:methanol=80:1~30 : 1 gradient elution), to obtain off-white solid 185mg, yield 50.6%. m.p.159-161℃. 1 H NMR (300MHz, DMSO-d 6 )δ (ppm): 12.61 (1H, s, CONH), 8.61 (1H, s, ArH), 8.27 (1H, d, J = 7.4Hz, ArH), 7.97 (1H, d, J = 7.4Hz, ArH ),7.91-7.80(2H,m,ArH),7.47-7.43(1H,m,ArH),7.39(1H,dd,J=6.4,1.9Hz,ArH),7.25(1H,t,J=9.0Hz ,ArH),6.97(2H,s,NH 2 ),6.82(1H,s,ArH),4.34(2H,s,ArCH 2 ),3.85-3.63(14H,m,2CH 2 O,5CH 2 N),3.24-3.21(2H,m,CH 2 N). 13 C-NMR (75MHz, DMSO-d 6 )δ(ppm):169.46,164.03,161.18,159.34,158.00,154.75,152.56,144.81,135.87,134.81,133.40,...

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Abstract

The invention relates to the field of medicinal chemistry, and specifically relates to a kind of PARP (poly-ADP-ribose polymerase)-1 and PI3K (phosphatidylinositol-3-kinase) dual target inhibitors (I)containing phthalazine-1(2H)-ketone and triazine or pyrimidine structures, preparation methods of the inhibitors, as well as pharmaceutical compositions containing compounds. It is proved, by pharmacodynamic tests, that the compounds involved in the invention have anti-tumor effects. The dual target inhibitors (I) are shown in the description.

Description

technical field [0001] The invention relates to the field of medicinal chemistry, in particular to a class of PARP-1 and PI3K dual-target inhibitors containing phthalazin-1(2H)-one and triazine or pyrimidine structures, their preparation methods, and drugs containing these compounds Composition and its use in antitumor. Background technique [0002] Poly ADP-ribose polymerase (PARP) is a multifunctional protein post-translational modification enzyme present in most eukaryotic cells. There are currently 18 subtypes in this family, among which PARP-1 accounts for the largest proportion. , involving the treatment of diseases such as stroke, neurodegenerative diseases, myocardial ischemia, cancer, inflammation and diabetes, and plays a leading role in DNA damage repair. PARP-1 inhibitors are a class of antitumor drugs that exert cytotoxicity by regulating DNA damage repair, and are one of the most exciting achievements in the field of tumor treatment research in the early 21st ...

Claims

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Application Information

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IPC IPC(8): C07D403/14C07D401/14C07D403/12C07D413/14A61K31/5377A61P35/00
Inventor 徐云根朱启华王均伟李慧葛亦然彭珂文
Owner CHINA PHARM UNIV
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