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PARP-1/PI3K double-target inhibitor or pharmaceutically acceptable salt thereof, preparation method and application thereof

A PARP-1, dual-target technology, applied in organic chemistry, drug combination, antineoplastic drugs, etc., can solve the problem of poor control of dosage, uneven pharmacokinetic properties, drug interaction and side effects, etc. problem, to achieve significant dual inhibitory effects, reduce drug resistance, and reduce drug dosage

Active Publication Date: 2021-06-29
CHINA PHARM UNIV +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the disadvantages of this combination drug include: the dosage is not well controlled; the pharmacokinetic properties are not uniform; and the interaction between drugs and the resulting toxic and side effects are prone to occur

Method used

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  • PARP-1/PI3K double-target inhibitor or pharmaceutically acceptable salt thereof, preparation method and application thereof
  • PARP-1/PI3K double-target inhibitor or pharmaceutically acceptable salt thereof, preparation method and application thereof
  • PARP-1/PI3K double-target inhibitor or pharmaceutically acceptable salt thereof, preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0042]2-(4-((2-(2-aminopyrimidin-5-yl)-7-methyl-4-morpholine substituted thieno[3,2-d]pyrimidin-6-yl)methyl)piperazine Synthesis of -1-carbonyl)benzofuran-7-carboxamide (I-1)

[0043] 2-(4-((2-chloro-7-methyl-4-morpholine substituted thieno[3,2-d]pyrimidin-6-yl)methyl)piperazine-1-carbonyl)benzofuran- Synthesis of 7-formamide (IV-1)

[0044] Take 4-(2-chloro-7-methyl-6-(piperazin-1-ylmethyl)thieno[3,2-d]pyrimidin-4-yl)morpholine (III-1, 7.00g, 17.00mmol), 7-formamidobenzofuran-2-carboxylic acid (II-1, 3.50g, 17.00mmol), PyBOP (10.70g, 0.021mol) were dissolved in 150mL DMF, slowly dropped into DIEA (11.25mL, 0.068mol), the reaction solution gradually changed from a white turbid solution to a yellow clear solution. The reaction was carried out at 25° C. for 6 h, and the reaction of raw materials was monitored by TLC (dichloromethane:methanol=15:1) to complete the reaction. The reaction was stopped, and 450 mL of water was slowly added at 0°C. A large amount of white solid w...

Embodiment 2

[0052] 2-(4-((2-(6-amino-4-(trifluoromethyl)pyridin-3-yl)-7-methyl-4-morpholine substituted thieno[3,2-d]pyrimidine- Synthesis of 6-yl)methyl)piperazine-1-carbonyl)benzofuran-7-carboxamide (I-2)

[0053] Substitution of 2-(4-((2-chloro-7-methyl-4-morpholine) thieno[3,2-d]pyrimidin-6-yl)methyl)piperazine-1-carbonyl)benzofuran -7-formamide (IV-1, 150mg, 0.27mmol) and 2-amino-4-trifluoromethyl-5-pyridine boronate (V-2, 94mg, 0.32mmol) are raw materials, and the operation process is the same as Synthetic process of compound I-1, 80 mg of white solid was obtained, yield 43.50%. m.p.138-140°C.

[0054] 1 H-NMR (300MHz, DMSO-d 6 )δ (ppm): 8.57 (s, 1H, ArH), 7.89 (d, J=7.7Hz, 1H, ArH), 7.85-7.75 (m, 2H, ArH, CONH 2 ), 7.71(s, 1H, CONH 2 ), 7.50(s, 1H, ArH), 7.42(t, J=7.5Hz, 1H, ArH), 6.85(s, 1H, ArH), 6.80(s, 2H, NH 2 ), 4.00-3.67 (m, 14H, ArCH 2 , CH 2 -O-CH 2 , 2CH 2 -N-CH 2 ), 2.62 (s, 4H, CH 2 -N-CH 2 ), 2.33 (s, 3H, CH 3 ).

[0055] HRMS(ESI):m / z[M+H] + .Calcd fb...

Embodiment 3

[0057] 4-(3-(4-((2-(2-aminopyrimidin-5-yl)-7-methyl-4-morpholine substituted thieno[3,2-d]pyrimidin-6-yl)methyl )Synthesis of piperazine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one (I-3)

[0058] 4-(3-(4-((2-chloro-7-methyl-4-morpholine substituted thieno[3,2-d]pyrimidin-6-yl)methyl)piperazine-1-carbonyl)- Synthesis of 4-fluorobenzyl)phthalazin-1(2H)-one (IV-2)

[0059] With 5-[(3,4-dihydro-4-oxo-1-phthalazinyl)methyl]-2-fluorobenzoic acid (II-2, 6.77g, 0.023mol) and 4-(2-chloro -7-Methyl-6-(piperazin-1-ylmethyl)thieno[3,2-d]pyrimidin-4-yl)morpholine hydrochloride (III-1, 10.0g, 0.023mol) is The raw material and the operation process were the same as the synthesis process of compound IV-1 to obtain 12.00 g of off-white solid with a yield of 82.50% and m.p.96-98°C.

[0060] 1 H-NMR (300MHz, DMSO-d 6 )δ(ppm): 12.64(s, 1H, CONH), 8.28(d, J=7.9Hz, 1H, ArH), 8.00(s, 1H, ArH), 7.91(t, J=7.6Hz, 1H, ArH ), 7.84(t, J=7.3Hz, 1H, ArH), 7.50-7.42(m, 1H, ArH), 7.36(dd, J=6.3Hz, 1...

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Abstract

The invention discloses a PARP-1 / PI3K double-target inhibitor or a pharmaceutically acceptable salt thereof, a preparation method and application thereof. According to the invention, the single active component can play a dual inhibition role on PARP-1 and PI3K, so that the dosage is reduced, the treatment effect is improved, and the toxic and side effects are reduced; and the dual inhibition effect on PARP-1 and PI3K is significant, the IC50 value of each target does not exceed 1.0 [mu]M, and the drug using the PARP-1 / PI3K double-target inhibitor as the active component can be used for treating a variety of cancers or tumors related to PARP-1 and / or PI3K.

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 or pharmaceutically acceptable salts thereof, preparation methods and uses. [0002] technical background [0003] The main mechanism of action of polyadenosine diphosphate-ribose transferase-1 (Poly (ADP-ribose) polymerase-1, PARP-1) inhibitors is synergistic lethality, so tumor cells with homologous recombination gene deletion or mutation use PARP- 1 inhibitors have the best therapeutic effect. For example, when PARP-1 inhibitors are used to block single-strand DNA damage repair in tumor cells with BRCA-1 / 2 mutations, synergistic lethality can be formed, eventually leading to cell death. Currently, four PARP-1 inhibitors have been approved for marketing, namely Olaparib, Rucaparib, Niraparib and Talazoparib. In addition, there are a variety of PARP-1 inhibitors in the clinical research stage. However, with the deepening of re...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D495/04A61P35/00
CPCC07D495/04A61P35/00
Inventor 徐云根何广卫吴正阳柏英朱启华莫佳佳储昭兴
Owner CHINA PHARM UNIV
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